EP3593800A1 - 1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof - Google Patents

1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof Download PDF

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Publication number
EP3593800A1
EP3593800A1 EP19179748.9A EP19179748A EP3593800A1 EP 3593800 A1 EP3593800 A1 EP 3593800A1 EP 19179748 A EP19179748 A EP 19179748A EP 3593800 A1 EP3593800 A1 EP 3593800A1
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EP
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Prior art keywords
alkyl
mmol
group
pyridin
brs
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EP19179748.9A
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German (de)
French (fr)
Inventor
John Hood
Sunil Kumar Kc
David Mark Wallace
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Biosplice Therapeutics Inc
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Samumed LLC
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Definitions

  • This invention relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of a 1H-pyrazolo[3,4- b ]pyridine compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis and idiopathic pulmonary fibrosis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases. Also provided are methods for treating Wnt-related disease states.
  • Wnt pathway signaling e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis and idiopathic pulmonary fibrosis
  • Wnt pathway signaling e.g., cancer, abnormal cellular proliferation
  • Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. Speculation on the mechanisms underlying these patterning effects usually centers on the secretion of a signaling molecule that elicits an appropriate response from the tissues being patterned. More recent work aimed at the identification of such signaling molecules implicates secreted proteins encoded by individual members of a small number of gene families.
  • cancer stem cells which may constitute only a minority of the cells within a tumor but are nevertheless critical for its propagation.
  • Stem cells are appealing as the cell of origin for cancer because of their pre-existing capacity for self-renewal and for unlimited replication.
  • stem cells are relatively long-lived in comparison to other cells within tissues, providing a greater opportunity to accumulate the multiple additional mutations that may be required to increase the rate of cell proliferation and produce clinically significant cancers.
  • Wnt signaling pathway which has been implicated in stem cell self-renewal in normal tissues, upon continuous activation has also been associated with the initiation and growth of many types of cancer. This pathway thus provides a potential link between the normal self-renewal of stem cells and the aberrantly regulated proliferation of cancer stem cells.
  • the Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human.
  • Members of the Wnt family of signaling molecules mediate many important short-and long-range patterning processes during invertebrate and vertebrate development.
  • the Wnt signaling pathway is known for its important role in the inductive interactions that regulate growth and differentiation, and plays important roles in the homeostatic maintenance of post-embryonic tissue integrity.
  • Wnt stabilizes cytoplasmic ⁇ -catenin, which stimulates the expression of genes including c-myc, c jun, fra-1, and cyclin Dl.
  • misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. More recently, the Wnt pathway has been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues that now includes skin, blood, gut, prostate, muscle and the nervous system.
  • Wnt pathway Pathological activation of the Wnt pathway is also believed to be the initial event leading to colorectal cancer in over 85% of all sporadic cases in the Western world. Activation of the Wnt pathway has also been extensively reported for hepatocellular carcinoma, breast cancer, ovarian cancer, pancreatic cancer, melanomas, mesotheliomas, lymphomas and leukemias.
  • inhibitors of the Wnt pathway can be used for stem cell research or for the treatment of any diseases characterized by aberrant Wnt activation such as idiopathic pulmonary fibrosis (IPF), diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis as well as mycotic and viral infections and bone and cartilage diseases.
  • IPF idiopathic pulmonary fibrosis
  • neovascular glaucoma neovascular glaucoma
  • rheumatoid arthritis psoriasis
  • mycotic and viral infections and bone and cartilage diseases.
  • Idiopathic pulmonary fibrosis is a ravaging condition of progressive lung scarring and destruction. This is a chronic, progressive, usually fatal, lung disease characterized by excessive fibrosis which causes eventual deterioration of the lung's architecture [ Nature Reviews Drug Discovery (2010), 9(2), 129-140 ]. Recently, the Wnt/ ⁇ -catenin pathway has become implicated in the etiology of the disease [ Annals of the Rheumatic Diseases (2012), 71(5), 761-767 ; Respiratory Research (2012), 13(3), pp. 9].
  • alpha-thalassemia (ATRX) syndrome [ The Journal of Neuroscience (2008), 28(47), 12570 -12580 ], fragile X syndrome [ PLoS Genetics (2010), 6(4), e1000898 ], ICF syndrome, Angelman syndrome [ Brain Research Bulletin (2002), 57(1), 109-119 ], Prader-Willi syndrome [ Journal of Neuroscience (2006), 26(20), 5383-5392 ], Beckwith-Wiedemann Syndrome [ Pediatric and Developmental Pathology (2003), 6(4), 299-306 ] and Rett syndrome.
  • ATRX alpha-thalassemia
  • Wnt pathway modulates in neural tissue, among other things, axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnt pathway activates and/or regulates diverse signaling pathways and other processes that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. Indeed, neuronal activity regulates the release of various Wnt proteins and the localization of their receptors. Wnt pathway mediates synaptic structural changes induced by neuronal activity or experience.
  • the present invention makes available methods and reagents, involving contacting a cell with an agent, such as a 1H-pyrazolo[3,4- b ]pyridine compound, in a sufficient amount to antagonize Wnt activity, e. g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components.
  • an agent such as a 1H-pyrazolo[3,4- b ]pyridine compound
  • Some embodiments disclosed herein include Wnt inhibitors containing a 1H-pyrazolo[3,4- b ]pyridine core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.
  • Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of general Formulas ( I ) or ( II ).
  • Some embodiments include pro-drugs of a compound of general Formulas ( I ) or ( II ).
  • compositions comprising a compound of general Formulas ( I ) or ( II ) and a pharmaceutically acceptable carrier, diluent, or excipient.
  • inventions disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a subject affected by a disorder or disease in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, cell cycling and mutations in Wnt signaling components, a compound according to Formulas ( I ) or ( II ). Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct a genetic disorder due to mutations in Wnt signaling components.
  • Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-ameliasyndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth
  • Another embodiment disclosed herein includes a pharmaceutical composition that has a compound according to any of the above formulas and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Some embodiments of the present invention include methods to prepare a compound of general Formulas ( I ) or ( II ).
  • compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins would be of tremendous benefit. Certain embodiments provide such compositions and methods. Certain related compounds and methods are disclosed in U.S. Application Ser. No. 12/968,505, filed December 15, 2010 , which claims priority to U.S. Provisional Application Ser. No. 61/288,544 , all of which are incorporated by reference in their entirety herein.
  • Some embodiments relate to a method for treating a disease including, but not limited to, cancers, diabetic retinopathy, idiopathic pulmonary fibrosis, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth
  • compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by the pathological activation or mutations of the Wnt pathway.
  • the composition includes a pharmaceutically acceptable carrier and a Wnt pathway inhibitor as described herein.
  • alkyl means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl, sec-butyl, tert -butyl, n-pentyl, tert -pentyl, neopentyl, isopentyl and sec-pentyl.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, thio, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, heterocyclyl, carbocyclyl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • Carbocyclyl means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
  • Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents, e.g., alkyl, halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents e.g., alkyl, halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • substituents e.g., alkyl, halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxy
  • lower alkyl means a subset of alkyl, and thus is a hydrocarbon substituent, which is linear or branched. Preferred lower alkyls are of 1 to about 3 carbons, and may be branched or linear. Examples of lower alkyl include n-propyl, isopropyl, ethyl, and methyl. Likewise, radicals using the terminology “lower” refer to radicals preferably with 1 to about 3 carbons in the alkyl portion of the radical.
  • amido means a H-CON- or alkyl-CON-, carbocyclyl-CON-, aryl-CON-, heteroaryl-CON- or heterocyclyl-CON group wherein the alkyl, carbocyclyl, heteroaryl, aryl or heterocyclyl group is as herein described.
  • aryl means an aromatic radical having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) with only carbon atoms present in the ring backbone.
  • Aryl groups can either be unsubstituted or substituted with one or more substituents, e.g., alkyl, amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
  • a preferred carbocyclic aryl is phenyl.
  • heteroaryl means an aromatic radical having one or more heteroatom(s) (e.g., N, O, or S) in the ring backbone and may include a single ring (e.g., pyridine) or multiple condensed rings (e.g., quinoline). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents, e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
  • substituents e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents.
  • heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridinyl, quin
  • substitution on the aryl and heteroaryl rings is within the scope of certain embodiments.
  • the radical is called substituted aryl or substituted heteroaryl.
  • substituents Preferably one to three and more preferably one or two substituents occur on the aryl or heteroaryl ring.
  • preferred substituents include those commonly found in aryl or heteroaryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, mercapto and the like.
  • amide includes both RNR'CO- and RCONR'-.
  • R can be substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted carbocyclyl.
  • R' can be H or substituted or unsubstituted alkyl.
  • halo is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. Most preferred halide is fluorine.
  • haloalkyl means a hydrocarbon substituent, which is linear or branched or cyclic alkyl, alkenyl or alkynyl substituted with chloro, bromo, fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbons in length, more preferred haloalkyls are 1 to about 2 carbons, and most preferred are 1 carbon in length.
  • haloalkylene means a diradical variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another functional group.
  • heterocyclyl means a cyclic ring system comprising at least one heteroatom in the ring system backbone.
  • Heterocyclyls may include multiple fused rings.
  • Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic.
  • Heterocyclyls may be substituted or unsubstituted with one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, and other substituents, and are attached to other groups via any available valence, preferably any available carbon or nitrogen. More preferred heterocycles are of 5-7 members.
  • the heteroatom(s) are selected from one up to three of O, N or S, and wherein when the heterocycle is five membered, preferably it has one or two heteroatoms selected from O, N, or S.
  • heterocyclyl examples include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5- b ]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl,
  • substituted amino means an amino radical which is substituted by one or two alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groups, wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.
  • sulfonamido means an alkyl-S(O) 2 N-, aryl-S(O) 2 N-, heteroaryl-S(O) 2 N-, carbocyclyl-S(O) 2 N- or heterocyclyl-S(O) 2 N- group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described.
  • rings As used herein, when two groups are indicated to be “linked” or “bonded” to form a “ring,” it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring.
  • rings can and are readily formed by routine chemical reactions, and it is within the purview of the skilled artisan to both envision such rings and the methods of their formations.
  • the term "ring” or “rings” when formed by the combination of two radicals refers to heterocyclic, carbocyclic, aryl, or heteroaryl rings.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompasses diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
  • administering refers to a method of giving a dosage of a compound or pharmaceutical composition comprising the same to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into
  • a “diagnostic” as used herein is a compound, method, system, or device that assists in the identification and characterization of a health or disease state.
  • the diagnostic can be used in standard assays as is known in the art.
  • mamal is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • various adjuvants such as are commonly used in the art may be included.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable.
  • the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297 .
  • Solidvate refers to the compound formed by the interaction of a solvent and a Wnt pathway inhibitor, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • Subject as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • terapéuticaally effective amount or “pharmaceutically effective amount” of a compound as provided herein is one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound.
  • “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula ( I ) in combination with one or more other agents that are effective to inhibit Wnt related diseases and/or conditions.
  • the combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou, Cancer Research (2010), 70(2), 440-446 , occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • a therapeutic effect relieves, to some extent, one or more of the symptoms of the disease, and includes curing a disease. "Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).
  • Treatment refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes.
  • therapeutic treatment refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder and/or reducing the severity of symptoms that will or are expected to develop.
  • Drug-eluting and or controlled release refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug-eluting material pass therefrom over time into the surrounding body tissue.
  • Drug-eluting material and or controlled release material as used herein refers to any natural, synthetic or semi-synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time.
  • “Elutable drug” as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body.
  • the compounds and compositions described herein can be used as anti-proliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, e.g., for treating diseases or disorders associated with aberrant Wnt signaling.
  • the compounds can be used as inhibitors of one or more kinases, kinase receptors, or kinase complexes.
  • Such compounds and compositions are also useful for controlling cellular proliferation, differentiation, and/or apoptosis.
  • Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or pro-drugs thereof of Formula ( I ):
  • R 3 is selected from the group consisting of H, halide and lower alkyl.
  • R 1 , R 2 and R 3 are H.
  • each R 6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C 1-9 alkyl, halide, CF 3 and CN.
  • each R 7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C 1-9 alkyl, halide, CF 3 and CN.
  • R 8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, -(C 1-3 alkyl) n arylR 6 , and -C 1-4 alkyl.
  • each R 9 is independently selected from the group consisting of H, -C 1-9 alkyl, -(C 1-3 alkyl) n aryl(R 6 ) q , -(C 1-3 alkyl) n carbocyclyl and -(C 1-9 alkyl)N(R 16 ) 2 .
  • two adjacent R 9 or two adjacent R 12 may be taken together with the atoms to which they are attached to form a heterocyclyl(R 17 ) q .
  • R 10 is selected from the group consisting of H, -CF 3 , -(C 1-3 alkyl) n aryl(R 6 ) q , and -C 1-9 alkyl.
  • R 11 is selected from the group consisting of -(C 1-3 alkyl) n aryl(R 6 ) q , -(C 1-3 alkyl) n carbocyclyl, -C 1-9 alkyl and -CF 3 .
  • each R 12 is independently selected from the group consisting of H, -(C 1-9 alkyl) n aryl(R 6 ) q and -C 1-9 alkyl.
  • each R 13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, -CF 3 , CN, -(C 1-3 alkyl) n heterocyclyl(R 8 ) q , -(C 1-9 alkyl) n N(R 9 ) 2 and -(C 1-9 alkyl) n NHSO 2 R 18 .
  • each R 14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF 3 and CN.
  • each R 16 is independently selected from the group consisting of H and lower alkyl.
  • each R 17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C 1-9 alkyl) n aryl(R 6 ) q , and -C 1-9 alkyl.
  • each R 18 is a lower alkyl.
  • A is N or C.
  • each q is an integer of 1 to 5.
  • each n is an integer of 0 or 1.
  • Formula I is not a structure selected from the group consisting of:
  • A is C.
  • A is N and R 2 is nil.
  • A is N; and R 1 and R 3 are both H.
  • aryl is phenyl
  • heteroaryl is pyridinyl
  • heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
  • R 2 is -CH 2 N(R 9 ) 2 or -N(R 9 ) 2 .
  • R 9 is independently selected from the group consisting of H, Me, Et, -CH 2 phenyl and -CH 2 carbocyclyl.
  • R 11 is selected from the group consisting of -C 1-5 alkyl, carbocyclyl, phenyl(R 6 ) q , and -CH 2 phenyl(R 6 ) q .
  • R 4 is phenyl(R 13 ) q .
  • R 4 is -heterocyclyl(R 14 ) q .
  • R 4 is -heteroaryl(R 15 ) q .
  • R 13 is one substituent attached to the phenyl comprising a fluorine atom.
  • R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a -(CH 2 ) n N(R 5 ) 2 or a-(CH 2 ) n NHSO 2 R 18 .
  • the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; and the R 14 is H or Me.
  • the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; and R 15 is lower alkyl or halide.
  • Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or pro-drugs thereof of Formula ( II ):
  • R 3 is selected from the group consisting of H, halide and lower alkyl.
  • R 1 , R 2 and R 3 are H.
  • each R 6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C 1-9 alkyl, halide, CF 3 and CN.
  • each R 7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C 1-9 alkyl, halide, CF 3 and CN.
  • each R 8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, -(C 1-3 alkyl) n aryl(R 6 ) q , and -C 1-4 alkyl.
  • each R 9 is independently selected from the group consisting of H, -C 1-9 alkyl, -(C 1-3 alkyl) n aryl(R 6 ) q , -(C 1-3 alkyl) n carbocyclyl and -(C 1-9 alkyl)N(R 16 ) 2 .
  • two adjacent R 9 or two adjacent R 12 may be taken together with the atoms to which they are attached to form a heterocyclyl(R 17 ) q .
  • R 10 is selected from the group consisting of H, -CF 3 , -(C 1-3 alkyl) n aryl(R 6 ) q , and -C 1-9 alkyl.
  • R 11 is selected from the group consisting of -(C 1-3 alkyl) n aryl(R 6 ) q , -(C 1-3 alkyl) n carbocyclyl, -C 1-9 alkyl and -CF 3 .
  • each R 12 is independently selected from the group consisting of H, -(C 1-9 alkyl) n aryl(R 6 ) q and -C 1-9 alkyl.
  • each R 13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, -CF 3 , CN, -(C 1-3 alkyl) n heterocyclyl(R 8 ) q , -(C 1-9 alkyl) n N(R 9 ) 2 and -(C 1-9 alkyl) n NHSO 2 R 18 .
  • each R 14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF 3 and CN.
  • each R 16 is independently selected from the group consisting of H and lower alkyl.
  • each R 17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C 1-9 alkyl) n aryl(R 6 ) q , and -C 1-9 alkyl.
  • each R 18 is a lower alkyl.
  • A is N or C.
  • each q is an integer of 1 to 5.
  • each n is an integer of 0 or 1.
  • Formula II is not a structure selected from the group consisting of:
  • A is C.
  • A is N and R 2 is nil.
  • A is N; and R 1 and R 3 are both H.
  • aryl is phenyl
  • heteroaryl is pyridinyl
  • heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
  • R 2 is -CH 2 N(R 9 ) 2 or -N(R 9 ) 2 .
  • R 9 is independently selected from the group consisting of H, Me, Et, -CH 2 phenyl and -CH 2 carbocyclyl.
  • R 11 is selected from the group consisting of -C 1-5 alkyl, carbocyclyl, phenyl(R 6 ) 2 , and -CH 2 phenyl(R 6 ) q .
  • R 4 is phenyl(R 13 ) q .
  • R 4 is -heterocyclyl(R 14 ) q .
  • R 4 is -heteroaryl(R 15 ) q .
  • R 13 is one substituent attached to the phenyl comprising a fluorine atom.
  • R 13 is two substituents each attached to the phenyl comprising a fluorine atom and either a -(CH 2 ) n N(R 5 ) 2 or a-(CH 2 ) n NHSO 2 R 18 .
  • the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; and the R 14 is H or Me.
  • the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; and R 15 is lower alkyl or halide.
  • R 3 is lower alkyl; and R 1 and R 2 are both H.
  • R 2 is
  • R 2 is -NH(C 1-3 alkyl).
  • R 2 is -N(C 1-3 alkyl) 2 .
  • R 2 is -NH 2 .
  • R 4 is pyridinyl
  • R 4 is furyl
  • R 4 is thiophenyl
  • R 4 is imidazolyl
  • R 4 is piperazinyl
  • R 4 is piperidinyl
  • R 4 is 1-methylpiperazinyl
  • R 4 is selected from the group consisting of:
  • R 11 is cyclopropyl
  • R 11 is cyclobutyl
  • R 11 is cyclopentyl
  • R 11 is cyclohexyl
  • R 13 is 1-2 fluorine atoms.
  • R 13 is -(C 1-6 alkyl)NHSO 2 R 11 .
  • R 13 is -(C 1-4 alkyl)NHSO 2 R 11 .
  • R 13 is -(C 1-2 alkyl)NHSO 2 R 11 .
  • R 13 is-CH 22 NHSO 2 R 11 .
  • R 13 is-CH 2 NHSO 2 CH 3 .
  • R 13 is -NR 12 (C 1-6 alkyl)NR 11 R 12 .
  • R 13 is -NR 12 (C 1-4 alkyl)NR 11 R 12 .
  • R 13 is - NR 12 CH 2 CH 2 NR 11 R 12 .
  • R 13 is-NHCH 2 CH 2 NR 11 R 12 .
  • R 13 is-NHCH 2 CH 2 N(CH 3 ) 2 .
  • R 13 is 2 substituents consisting of 1 fluorine atom and -NR 12 (C 1-6 alkyl)NR 11 R 12 .
  • R 13 is 2 substituents consisting of 1 fluorine atom and -NHCH 2 CH 2 NR 11 R 12 ,
  • R 13 is 2 substituents consisting of 1 fluorine atom and -(C 1-6 alkyl)NHSO 2 R 11 .
  • R 13 is 2 substituents consisting of 1 fluorine atom and -CH 2 NHSO 2 R 11 .
  • R 15 is Me.
  • R 15 is halide
  • R 15 is fluorine
  • q is an integer ranging from 1 to 5, preferably 1 or 3, more preferably 1-2.
  • A is C; R 1 , R 2 and R 3 are all H; R 4 is selected from the group consisting of pyridine and -heterocyclyl(R 14 ) q ; q is 1 or 2 and R 14 is selected from the group consisting of H, F and -(C 1-4 alkyl).
  • A is C; R 1 and R 3 are H; R 2 is amino; R 4 is selected from the group consisting of -phenyl(R 13 ) q and-heterocyclyl(R 14 ) q , -heteroaryl(R 15 ) q ; q is 1 or 2; R 15 is H; R 14 is selected from the group consisting of H, F and -(C 1-4 alkyl); R 13 is 1-2 fluorine atoms; and the heteroaryl is selected from the group consisting of pyridine, furan and thiophene.
  • compositions comprising: (a) a safe and therapeutically effective amount of the 1H-pyrazolo[3,4- b ]pyridine compound, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.
  • the compounds of this invention may also be useful in combination (administered together or sequentially) with other known agents.
  • Non-limiting examples of diseases which can be treated with a combination of a compound of Formulas ( I ) or ( II ) and other known agents are colorectal cancer, ovarian cancer, retinitis pigmentosa, macular degeneration, idiopathic pulmonary fibrosis and osteoarthritis.
  • colorectal cancer can be treated with a combination of a compound of either Formulas ( I ) or ( II ) and one or more of the following drugs: 5-Fluorouracil (5-FU), which is often given with the vitamin-like drug leucovorin (also called folinic acid); Capecitabine (Xeloda®), Irinotecan (Camptosar®), Oxaliplatin (Eloxatin®).
  • 5-Fluorouracil 5-FU
  • leucovorin also called folinic acid
  • Capecitabine Xeloda®
  • Irinotecan Piertosar®
  • Oxaliplatin Oxaliplatin
  • Examples of combinations of these drugs which could be further combined with a compound of either Formulas ( I ) or ( II ) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin).
  • FOLFOX 5-FU, leucovorin, and oxaliplatin
  • FOLFIRI 5-FU, leucovorin, and irinotecan
  • FOLFOXIRI leucovorin, 5-FU, oxaliplatin, and irinotecan
  • CapeOx CapeOx
  • chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).
  • ovarian cancer can be treated with a combination of a compound of either Formulas ( I ) or ( II ) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (Doxil®), Gemcitabine (Gemzar®), Cyclophosphamide (Cytoxan®), Vinorelbine (Navelbine®), Ifosfamide (Ifex®), Etoposide (VP-16), Altretamine (Hexalen®), Capecitabine (Xeloda®), Irinotecan (CPT-11, Camptosar®), Melphalan, Pemetrexed (Alimta®) and Albumin bound paclitaxel (nab-paclitaxel, Abraxane®).
  • Topotecan Liposomal doxorubicin (Doxil®), Gemcitabine (Gemzar®), Cyclophosphamide (Cytoxan®), Vinorelbine (Navelbine®), Ifo
  • Examples of combinations of these drugs which could be further combined with a compound of either Formulas ( I ) or ( II ) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP (etoposide [VP-16], ifosfamide, and cisplatin).
  • TIP paclitaxel [Taxol], ifosfamide, and cisplatin
  • VeIP vinblastine, ifosfamide, and cisplatin
  • VIP etoposide [VP-16], ifosfamide, and cisplatin
  • a compound of either Formulas ( I ) or ( II ) can be used to treat cancer in combination with any of the following methods:
  • Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others;
  • Ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy and cryosurgery (cryotherapy);
  • RFA radiofrequency ablation
  • ethanol alcohol
  • cryotherapy Chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide;
  • Chemotherapy using anti-metabolites such as azathioprine and mercaptopurine;
  • e Chemotherapy using plant alkaloids and terpenoids such as vinca al
  • Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide;
  • Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin;
  • Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate (Gleevec®, also known as STI-571), Gefitinib (Iressa, also known as
  • PARP inhibitors e.g. Iniparib, Olaparib in clinical trials
  • PI3K inhibitors e.g. perifosine in a phase III trial
  • VEGF Receptor 2 inhibitors e.g. Apatinib
  • AN-152 e.g. AEZS-108
  • Braf inhibitors e.g. vemurafenib, dabrafenib and LGX818
  • MEK inhibitors e.g. trametinib and MEK162
  • CDK inhibitors e.g.
  • PD-0332991 PD-0332991
  • salinomycin and Sorafenib
  • Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MabThera® or Rituxan®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as Erbitux®) and Bevacizumab (marketed as Avastin®); and
  • k radiation therapy.
  • idiopathic pulmonary fibrosis can be treated with a combination of a compound of either Formulas ( I ) or ( II ) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprine, N-acetylcysteine, interferon- ⁇ 1b, bosentan (bosentan is currently being studied in patients with IPF, [ The American Journal of Respiratory and Critical Care Medicine (2011), 184(1), 92-9 ]), Nintedanib (BIBF 1120 and Vargatef), QAX576 [ British Journal of Pharmacology (2011), 163(1), 141-172 ], and anti-inflammatory agents such as corticosteroids.
  • pirfenidone pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet®
  • prednisone azathioprine
  • a compound of either Formulas ( I ) or ( II ) can be used to treat idiopathic pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery.
  • a compound of either Formulas ( I ) or ( II ) can be used to treat osteoarthritis in combination with any of the following methods: ( a ) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; ( b ) physical therapy; ( c ) injections of corticosteroid medications; ( d ) injections of hyaluronic acid derivatives (e.g.
  • NSAIDs Nonsteroidal anti-inflammatory drugs
  • Hyalgan, Synvisc Hyalgan, Synvisc
  • ( h ) joint replacement (arthroplasty); and ( i ) in combination with a chronic pain class e.g., splints, braces, shoe inserts or other medical devices
  • ( h ) joint replacement (arthroplasty) i ) in combination with a chronic pain class.
  • macular degeneration can be treated with a combination of a compound of either Formulas ( I ) or ( II ) and one or more of the following drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®), Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfin (Visudyne®) in combination with photodynamic therapy (PDT) or with any of the following methods: ( a ) in combination with laser to destroy abnormal blood vessels (photocoagulation); and ( b ) in combination with increased vitamin intake of antioxidant vitamins and zinc.
  • retinitis pigmentosa can be treated with a combination of a compound of either Formulas ( I ) or ( II ) and one or more of the following drugs: UF-021 (OcusevaTM), vitamin A palmitate and pikachurin or with any of the following methods: ( a ) with the Argus® II retinal implant; and ( b ) with stem cell and/or gene therapy.
  • compositions as provided herein may be formulated as solids, semi solids, liquids, solutions, colloidals, liposomes, emulsions, suspensions, complexes, coacervates, or aerosols.
  • Dosage forms such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like are also provided herein.
  • compositions may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols.
  • Dosage forms such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like.
  • compositions may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention.
  • Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium
  • Cyclodextrins such as ⁇ -, ⁇ , and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds described herein.
  • Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from nontoxic carrier may be prepared.
  • the contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012 ).
  • the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a powder, marume, solution or suspension e.g ., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides
  • a capsule gelatin or cellulose base capsule
  • Unit dosage forms in which the two active ingredients are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g ., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension.
  • a carrier e.g ., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g ., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g ., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 0.25 mg/Kg to 50 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 0.25 mg/Kg to 20 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 0.50 mg/Kg to 19 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 0.75 mg/Kg to 18 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 1.0 mg/Kg to 17 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 1.25 mg/Kg to 16 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 1.50 mg/Kg to 15 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 1.75 mg/Kg to 14 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 2.0 mg/Kg to 13 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or ( II ) is 3.0 mg/Kg to 12 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) is 4.0 mg/Kg to 11 mg/Kg in humans.
  • the unit dosage of compounds of Formulas ( I ) or (II) is 5.0 mg/Kg to 10 mg/Kg in humans.
  • compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • compositions are provided in unit dosage forms suitable for twice a day administration of a precise dose.
  • compositions are provided in unit dosage forms suitable for three times a day administration of a precise dose.
  • Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection.
  • the percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.
  • the composition will comprise 0.1-10% of the active agent in solution.
  • the composition will comprise 0.1-5% of the active agent in solution.
  • the composition will comprise 0.1-4% of the active agent in solution.
  • the composition will comprise 0.15-3% of the active agent in solution.
  • the composition will comprise 0.2-2% of the active agent in solution.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-96 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-72 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-48 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-24 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-12 hours.
  • compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-6 hours.
  • compositions can be administered by intravenous infusion to humans at doses of 5 mg/m 2 to 300 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of 5 mg/m 2 to 200 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of 5 mg/m 2 to 100 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of 10 mg/m 2 to 50 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of 50 mg/m 2 to 200 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of 75 mg/m 2 to 175 mg/m 2 .
  • compositions can be administered by intravenous infusion to humans at doses of 100 mg/m 2 to 150 mg/m 2 .
  • concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
  • compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique.
  • respiratory tract including nasal and pulmonary
  • a nebulizer metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique.
  • aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose.
  • inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred.
  • a larger inhaled particle size is desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation.
  • aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth.
  • inhaled aerodynamic particle sizes of about less than 10 ⁇ m are useful, with an aerodynamic particle size of about 1 to about 10 microns being preferred.
  • Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.
  • compounds of Formulas (I) or (II) disclosed herein intended for respiratory delivery can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates or as dry powders.
  • Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose® or the AERx® systems).
  • Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs).
  • Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.
  • compositions of Formulas ( I ) or ( II ) disclosed herein can be administered to the ear by various methods.
  • a round window catheter e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873 .
  • formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484 ) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559 ).
  • formulations of the invention can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211 ).
  • compounds of Formulas ( I ) or ( II ) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.
  • compounds of Formulas ( I ) or ( II ) can be delivered from the reservoir of an external or internal implanted pumping system.
  • Formulations of the invention also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815 ).
  • Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear.
  • the formulations described herein are administered directly onto the round window membrane via transtympanic injection.
  • the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear.
  • the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
  • the compounds of Formulas ( I ) or ( II ) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria.
  • the solid composition is a single unit. This implies that one unit dose of the drug is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.
  • Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like.
  • the solid composition is a highly porous lyophilized form.
  • Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound.
  • the solid composition may also be formed as a multiple unit dosage form as defined above.
  • multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like.
  • the solid composition is a lyophilized powder.
  • Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution.
  • Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound.
  • Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles.
  • the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
  • kits typically include one or more compounds or compositions as described herein.
  • a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided above, and directions for use of the kit (e.g., instructions for treating a patient).
  • the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer.
  • the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Ro
  • the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • the compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more members of the Wnt pathway, which may include one or more Wnt proteins, and thus can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components.
  • Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, rheumatoid arthritis, scleroderma, sarcoidosis, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neuron disease, Down's syndrome, frontotemporal dementia (FTDP-17), Pick's disease, surpanuclear palsy, corticobasal degeneration, multiple sclerosis or autism, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, retinal tumors, early coronary disease, tetra-amelia,
  • the Wnt pathway is known to be constitutively activated in a variety of cancers including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer , pancreatic cancer and leukemias such as CML, CLL, T-ALL, myelodysplastic syndromes and Mantle Cell Lympohomas.
  • the constitutive activation is due to constitutively active ⁇ -catenin, perhaps due to its stabilization by interacting factors or inhibition of the degradation pathway.
  • the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated.
  • the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.
  • cancers can also be treated with the compounds and compositions described herein.
  • cancers that may be treated by the compound, compositions and methods described herein include, but are not limited to, the following:
  • Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term "tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders.
  • a method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy).
  • a compound or composition can be administered before, during, or after another anticancer agent or treatment.
  • the compounds and compositions described herein can be used as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular proliferation mediated by protein kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition.
  • the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient.
  • Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders.
  • such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells
  • Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following:
  • Non-limiting examples of neurological conditions/disorders/diseases which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP).
  • CIDP chronic fatigue syndrome
  • the compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.
  • the invention provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formulas ( I ) or ( II ), in combination (simultaneously or sequentially) with at least one other agent.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formulas ( I ) or ( II ), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formulas ( I ) or ( II ), or a pharmaceutically acceptable salt thereof.
  • the disorder or disease is cancer.
  • the disorder or disease is diabetic retinopathy.
  • the disorder or disease is pulmonary fibrosis.
  • the disorder or disease is idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the disorder or disease is rheumatoid arthritis.
  • the disorder or disease is scleroderma.
  • the disorder or disease is a mycotic or viral infection.
  • the disorder or disease is a bone or cartilage disease.
  • the disorder or disease is Alzheimer's disease.
  • the disorder or disease is dementia.
  • the disorder or disease is Parkinson's disease.
  • the disorder or disease is osteoarthritis.
  • the disorder or disease is lung disease
  • the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Mullerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader
  • the patient is a human.
  • the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.
  • CML chronic myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • acute myeloid leukemia acute lymphocytic leukemia
  • Hodgkin lymphoma lymphoma
  • lymphoma lymphoma
  • sarcoma sarcoma and ovarian cancer.
  • the cancer is chosen from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer - melanoma, small intestine cancer, stomach cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal
  • the cancer is hepatocellular carcinoma.
  • the cancer is colon cancer.
  • the cancer is breast cancer.
  • the cancer is pancreatic cancer.
  • the cancer is chronic myeloid leukemia (CML).
  • CML chronic myeloid leukemia
  • the cancer is chronic myelomonocytic leukemia.
  • the cancer is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • the cancer is acute myeloid leukemia.
  • the cancer is acute lymphocytic leukemia.
  • the cancer is Hodgkin lymphoma.
  • the cancer is lymphoma.
  • the cancer is sarcoma.
  • the cancer is ovarian cancer.
  • the cancer is lung cancer - non-small cell.
  • the cancer is lung cancer - small cell.
  • the cancer is multiple myeloma.
  • the cancer is nasopharyngeal cancer.
  • the cancer is neuroblastoma.
  • the cancer is osteosarcoma.
  • the cancer is penile cancer.
  • the cancer is pituitary tumors.
  • the cancer is prostate cancer.
  • the cancer is retinoblastoma.
  • the cancer is rhabdomyosarcoma.
  • the cancer is salivary gland cancer.
  • the cancer is skin cancer - basal and squamous cell.
  • the cancer is skin cancer - melanoma.
  • the cancer is small intestine cancer.
  • the cancer is stomach cancers.
  • the cancer is testicular cancer.
  • the cancer is thymus cancer.
  • the cancer is thyroid cancer.
  • the cancer is uterine sarcoma.
  • the cancer is vaginal cancer.
  • the cancer is vulvar cancer.
  • the cancer is Wilms tumor.
  • the cancer is laryngeal or hypopharyngeal cancer.
  • the cancer is kidney cancer.
  • the cancer is Kaposi sarcoma.
  • the cancer is gestational trophoblastic disease.
  • the cancer is gastrointestinal stromal tumor.
  • the cancer is gastrointestinal carcinoid tumor.
  • the cancer is gallbladder cancer.
  • the cancer is eye cancer (melanoma and lymphoma).
  • the cancer is Ewing tumor.
  • the cancer is esophagus cancer.
  • the cancer is endometrial cancer.
  • the cancer is colorectal cancer.
  • the cancer is cervical cancer.
  • the cancer is brain or spinal cord tumor.
  • the cancer is bone metastasis.
  • the cancer is bone cancer.
  • the cancer is bladder cancer.
  • the cancer is bile duct cancer.
  • the cancer is anal cancer.
  • the cancer is adrenal cortical cancer.
  • the disorder or disease is a neurological condition, disorder or disease, wherein the neurological condition/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and Charcot-Marie-Tooth disease.
  • the neurological condition/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism,
  • the compound of Formulas ( I ) or ( II ) inhibits one or more proteins in the Wnt pathway.
  • the compound of Formulas ( I ) or ( II ) inhibits signaling induced by one or more Wnt proteins.
  • the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.
  • the compound of Formulas ( I ) or ( II ) inhibits a kinase activity.
  • the method of treats a disease or disorder mediated by the Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas ( I ) or ( II ), or a pharmaceutically acceptable salt thereof.
  • the compound of Formulas ( I ) or ( II ) inhibits one or more Wnt proteins.
  • the method of treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas ( I ) or ( II ), or a pharmaceutically acceptable salt thereof.
  • the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.
  • the method of inhibits the activity of a protein kinase receptor comprises contacting the receptor with an effective amount of a compound (or compounds) of Formulas ( I ) or ( II ), or a pharmaceutically acceptable salt thereof.
  • the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas ( I ) or ( II ), or a pharmaceutically acceptable salt thereof.
  • the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas ( I ) or ( II ), or a pharmaceutically acceptable salt thereof.
  • the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas ( I ) or ( II ), or a pharmaceutically acceptable salt thereof.
  • the method of treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprising administering to the patient a pharmaceutical composition comprising one or more of the compounds of Formulas ( I ) or ( II ) in combination with a pharmaceutically acceptable carrier and one or more other agents
  • the compounds and compositions for example, as inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.
  • viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.
  • CDK/cyclin complexes such as those active in the G. 0 , G. 1 or mitotic stage of the cell cycle, e.g., CDK1, CDK2, CDK4, and/or CDK6 complexes.
  • the biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, e.g., WO 2001/053268 or WO 2005/009997 .
  • the activity of a compound may be tested using one or more of the test methods outlined below.
  • tumor cells may be screened for Wnt independent growth.
  • tumor cells of interest are contacted with a compound (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored.
  • tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway.
  • Candidate cancers include, without limitation, those listed above.
  • one may utilize in vitro assays for Wnt biological activity e.g. stabilization of ⁇ -catenin and promoting growth of stem cells.
  • Assays for biological activity of Wnt include stabilization of ⁇ -catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition.
  • An exemplary assay for Wnt biological activity contacts a Wnt composition in the presence of a candidate inhibitor with cells, e.g. mouse L cells. The cells are cultured for a period of time sufficient to stabilize ⁇ -catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for ⁇ -catenin.
  • the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay ( Leyns, L. et al. Cell (1997), 88(6), 747-756 ).
  • the peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; m, multiplet.
  • Scheme 1 describes a method for preparation of 1H-pyrazolo[3,4- b ]pyridine derivatives ( VIII ) by reacting aldehyde III with various boronic acid derivatives ( XII ) under Suzuki coupling conditions to give aldehyde V.
  • Aldehyde V is reacted with various substituted and unsubstituted aryl/heteroaryl-3,4-diamines ( VI ) to form VII .
  • Final deprotection of the pyrazolone nitrogen yields the desired 1H-pyrazolo[3,4- b ]pyridine derivative ( VIII ).
  • Scheme 2 describes an alternative method for preparation of 1H-pyrazolo[3,4- b ]pyridine derivatives ( VIII ) by reacting 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- b ]pyridine-3-carbaldehyde ( III ) with bis(pinacolato)diboron to form the borate ester ( IX ).
  • Suzuki coupling with various bromides ( X ) or chlorides yields 1H-pyrazolo[3,4- b ]pyridine derivatives ( V ).
  • Aldehyde ( V ) is reacted with various 1,2-diamines ( VI ) to produce ( VII ).
  • Final deprotection of the pyrazole nitrogen yields the desired 1H-pyrazolo[3,4- b ]pyridine derivatives ( VIII ).
  • the mixture was filtered through diatomaceous earth (14 Kg) followed by washing the diatomaceous earth with 3 x DCM (50 L).
  • the organic layer was separated, washed with aqueous 25% NaCl (200 L) and concentrated under vacuum to a volume of 70 L.
  • the product was crystallized by charging the solution with 3 x n-heptane (88 L) while concentrating the volume to 70 L after each addition of n-heptane.
  • the solid was filtered and washed 3 x n-heptane (22 L).
  • the solution was cooled to 0°C under nitrogen before the pH was adjusted to 1 with aqueous 35% HC1 ( ⁇ 75 L).
  • the solution was warmed to room temperature before adding n-BuOH (473 L) which was stirred for 25 min and then the organic layer was separated.
  • n-BuOH (473 L) was again added to the aqueous layer, stirred for 25 min and separated.
  • the combined organic phases were concentrated under vacuum to a volume of ⁇ 54 L.
  • the n-BuOH was removed by adding to the solution 9 x n-heptane (78 L) dropwise over 1 hour and then concentrating the volume to ⁇ 54 L after each addition of n-heptane.
  • the solid was filtered and washed 3 x n-heptane (17 L).
  • the product was crystallized by charging the solution with 3 x n-heptane (8 L) while concentrating the volume to 4.8 L after each addition of n-heptane.
  • the solid was filtered and dried under vacuum at 50°C to produce methyl 5-bromo-1H-pyrazolo[3,4- b ]pyridine-3-carboxylate ( XVII ) (1.53 Kg, 6.0 mol, 80.6% purity, 90.4% assay yield).
  • N-(5-Bromopyridin-3-yl)cyclopentanecarboxamide ( XL ): Yellow solid (1.9 g, 7.06 mmol, 80.2% yield).
  • N-(5-bromopyridin-3-yl)cyclohexanecarboxamide ( XLI ): Yellow solid (2.0 g, 7.06 mmol, 84.3% yield).
  • ESIMS found C 12 H 15 BrN 2 O m / z 283 (M+H).
  • the crude product was purified on a silica gel column (100% hexane ⁇ 90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine ( XLVI ) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield).
  • N-Benzyl-1-(5-bromopyridin-3-yl)methanamine ( LV ): Golden liquid (77 mg, 0.28 mmol, 25% yield).
  • ESIMS found for C 13 H 13 BrN 2 m / z 277 (M+H).
  • Triethylsilane 72 ⁇ L, 0.45 mmol
  • TFA 2.5 mL
  • the solvent was removed under vacuum. Water was added to the residue, sonicated briefly and basified with a 5N NH 4 OH solution. The solids formed were filtered, washed with cold water and dried at room temperature. The solids were boiled in DCM, cooled to room temperature and sonicated briefly.
  • Reporter cell lines can be generated by stably transducing cells of cancer cell lines (e.g., colon cancer) with a lentiviral construct that include a wnt-responsive promoter driving expression of the firefly luciferase gene.
  • cancer cell lines e.g., colon cancer
  • lentiviral construct that include a wnt-responsive promoter driving expression of the firefly luciferase gene.
  • Lentiviral constructs can be made in which the SP5 promoter, a promoter having eight TCF/LEF binding sites derived from the SP5 promoter, is linked upstream of the firefly luciferase gene.
  • the lentiviral constructs can also include a hygromycin resistance gene as a selectable marker.
  • the SP5 promoter construct can be used to transduce SW480 cells, a colon cancer cell line having a mutated APC gene that generates a truncated APC protein, leading to de-regulated accumulation of ⁇ -catenin.
  • a control cell line can be generated using another lentiviral construct containing the luciferase gene under the control of the SV40 promoter which does not require ⁇ -catenin for activation.
  • Cultured SW480 cells bearing a reporter construct can be distributed at approximately 10,000 cells per well into 96 well or 384 well plates. Compounds from a small molecule compound library can then be added to the wells in half-log dilutions using a ten micromolar top concentration. A series of control wells for each cell type receive only buffer and compound solvent. Twenty-four to forty hours after the addition of compound, reporter activity for luciferase can be assayed, for example, by addition of the BrightGlo luminescence reagent (Promega) and the Victor3 plate reader (Perkin Elmer). Readings can be normalized to DMSO only treated cells, and normalized activities can then be used in the IC 50 calculations. Table 2 shows the activity of selected compounds of the invention. Table 2.
  • Compound Wnt inhibition ( ⁇ M) Compound Wnt inhibition ( ⁇ M) Compound Wnt inhibition ( ⁇ M) 1 0.006 192 1.05 594 0.12 2 0.038 198 1.13 595 0.354 2 0.006 209 9.8 599 0.22 4 0.333 229 0.012 602 0.018 5 0.0039 238 0.35 605 0.018 6 0.55 241 0.19 616 1.41 7 0.006 246 1.27 621 0.036 8 8.25 249 10 635 0.034 9 0.0012 254 0.235 637 0.11 10 0.263 305 7.35 643 0.03 11 0.099 309 1.02 647 1.52 12 0.021 325 0.058 654 1.5 13 0.172 336 0.79 680 0.17 14 0.138 346 0.056 691 0.187 15 0.326 352 0.057 698 0.3 16 0.384 354 0.293 701 0.625 17 0.55 373 0.07 704 0.81 18 0.013 376 0.051 719 0.2 19 0.499
  • Preparation of a 220 ⁇ g/mL suspension in 0.5% CMC/0.05% tween 80 begins by dispensing 597 g ⁇ 1 g of Gibco 1X PBS into the 1 L glass bottle. Using a 1 mL sterile syringe, measure 0.3 mL of Tween 80. In a weigh boat, weigh out 3 g ⁇ 0.1 g of Carboxymethyl Cellulose 7LXF PH (CMC). Mix with the Tween80/PBS solution and slowly sprinkle the CMC into the 1 L bottle containing the PBS/Tween mixture (increase mixing speed as necessary). Once visually dispersed and the polymer is hydrated, start heating the container on a heating plate to promote phase inversion (turbidity).
  • CMC Carboxymethyl Cellulose 7LXF PH
  • Administration is performed using a 30G needle and a volume of approximately 50 ⁇ L for intravitreal injection in rabbits.
  • Administration is performed using a 25G needle and a volume of approximately 200 ⁇ L for intratympanic injection targeting the round window membrane.
  • IPF idiopathic pulmonary fibrosis
  • Administration is performed using a jet nebulizer (Pari LC plus) or an aerodose nebulizer.
  • C57B1/6 mice were dosed for 30 minutes via a nose only chamber (CH Technology) at a flow rate of 15 LPM, particle size distribution and dose was measured by a 7 stage impactor (1 LPM) placed in one of the ports. A median aerosol particle size of 1.2 ⁇ m with a GSD of 1.8 ⁇ m was obtained and a dosing rate of 1.5 ⁇ M/min/mouse. Table 5. Concentrations of a compound of Formulas (I) or (II) in Mice (C57B1/6) Inhalation Conc. (ng/mL) Time Point (h) Plasma Lung Ratio 0.25 21.9 467.2 21.3 2 0.8 400.1 500.1 6 8.8 392.5 44.6 23 0.03 260.7 8690
  • a diluted formulation of 0.5 mg/mL of compound of Formulas ( I ) or ( II ) was nebulized for 10 and 30 minutes to bleomycin-induced pulmonary fibrotic C57B1/6 mice.
  • Bleomycin is a chemotherapeutic agent which use has been shown to cause pulmonary fibrosis in humans.
  • it became widely used as a research tool to induce and study pulmonary fibrosis in animals [ Walters, D.M. and Kleeberger, S.R., "Mouse models of bleomycin-induced pulmonary fibrosis" Current Protocols in Pharmacology (2008) Chapter 5: Unit 5.46, 1-17 ].
  • PLGA microparticle formation Add 20 mL of solution 2 into a clean sterile container, while mixing (high speed mixing) slowly add the entire 4 mL of solution 1 to solution 2.

Abstract

Provided herein are compounds according to Formulas (I) or (II) and pharmaceutically acceptable salts thereof , and compositions comprising the same, for use in various methods, including treating cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis, idiopathic pulmonary fibrosis and neurological conditions/disorders/diseases.

Description

    RELATED APPLICATIONS Cross-Reference to Related Applications
  • This application claims the benefit of U.S. Provisional Application No. 61/642,915, filed May 4, 2012 , which is incorporated herein by reference in its entirety.
    • BACKGROUND OF THE INVENTION Field of the Invention
  • This invention relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins, and compositions comprising the same. More particularly, it concerns the use of a 1H-pyrazolo[3,4-b]pyridine compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis and idiopathic pulmonary fibrosis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases. Also provided are methods for treating Wnt-related disease states.
    • Description of the Related Art
  • Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. Speculation on the mechanisms underlying these patterning effects usually centers on the secretion of a signaling molecule that elicits an appropriate response from the tissues being patterned. More recent work aimed at the identification of such signaling molecules implicates secreted proteins encoded by individual members of a small number of gene families.
  • A longstanding idea in cancer biology is that cancers arise and grow due to the formation of cancer stem cells, which may constitute only a minority of the cells within a tumor but are nevertheless critical for its propagation. Stem cells are appealing as the cell of origin for cancer because of their pre-existing capacity for self-renewal and for unlimited replication. In addition, stem cells are relatively long-lived in comparison to other cells within tissues, providing a greater opportunity to accumulate the multiple additional mutations that may be required to increase the rate of cell proliferation and produce clinically significant cancers. Of particular recent interest in the origin of cancer is the observation that the Wnt signaling pathway, which has been implicated in stem cell self-renewal in normal tissues, upon continuous activation has also been associated with the initiation and growth of many types of cancer. This pathway thus provides a potential link between the normal self-renewal of stem cells and the aberrantly regulated proliferation of cancer stem cells.
  • The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human. Members of the Wnt family of signaling molecules mediate many important short-and long-range patterning processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its important role in the inductive interactions that regulate growth and differentiation, and plays important roles in the homeostatic maintenance of post-embryonic tissue integrity. Wnt stabilizes cytoplasmic β-catenin, which stimulates the expression of genes including c-myc, c jun, fra-1, and cyclin Dl. In addition, misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. More recently, the Wnt pathway has been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues that now includes skin, blood, gut, prostate, muscle and the nervous system.
  • Pathological activation of the Wnt pathway is also believed to be the initial event leading to colorectal cancer in over 85% of all sporadic cases in the Western world. Activation of the Wnt pathway has also been extensively reported for hepatocellular carcinoma, breast cancer, ovarian cancer, pancreatic cancer, melanomas, mesotheliomas, lymphomas and leukemias. In addition to cancer, inhibitors of the Wnt pathway can be used for stem cell research or for the treatment of any diseases characterized by aberrant Wnt activation such as idiopathic pulmonary fibrosis (IPF), diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis as well as mycotic and viral infections and bone and cartilage diseases. As such, it is a therapeutic target that is of great interest to the field.
  • Idiopathic pulmonary fibrosis (IPF) is a ravaging condition of progressive lung scarring and destruction. This is a chronic, progressive, usually fatal, lung disease characterized by excessive fibrosis which causes eventual deterioration of the lung's architecture [ Nature Reviews Drug Discovery (2010), 9(2), 129-140]. Recently, the Wnt/β-catenin pathway has become implicated in the etiology of the disease [Annals of the Rheumatic Diseases (2012), 71(5), 761-767; Respiratory Research (2012), 13(3), pp. 9]. At the cellular level, it is has been shown that β-catenin is overexpressed in bronchial epithelial cells which contributes to an epithelial to mesenchymal cell transition (EMT). This results in increased presence of proliferating fibroblasts and myofibroblasts which leads to excess collagen deposition in the lungs [ Respiratory Research (2012), 13(3), pp. 9]. The formation of these fibroblastic foci and increased extracellular matrix deposition are pathological hallmarks of IPF.
  • There are also many cases of genetic diseases due to mutations in Wnt signaling components. Examples of some of the many diseases are Alzheimer's disease [Proc. Natl. Acad. Sci. U S A (2007), 104(22), 9434-9], osteoarthritis, polyposis coli [Science (1991), 253(5020), 665-669], bone density and vascular defects in the eye (osteoporosis-pseudoglioma syndrome, OPPG) [N. Engl. J. Med. (2002), 346(20), 1513-21], familial exudative vitreoretinopathy [Hum. Mutat. (2005), 26(2), 104-12], retinal angiogenesis [ Nat. Genet. (2002), 32(2), 326-30], early coronary disease [Science (2007), 315(5816), 1278-82], tetra-amelia syndrome [ Am. J. Hum. Genet. (2004), 74(3), 558-63], Mullerian-duct regression and virilization [Engl. J. Med. (2004), 351(8), 792-8], SERKAL syndrome [ Am. J. Hum. Genet. (2008), 82(1), 39-47], diabetes mellitus type 2 [ Am. J. Hum. Genet. (2004), 75(5), 832-43; N. Engl. J. Med. (2006), 355(3), 241-50], Fuhrmann syndrome [ Am. J. Hum. Genet. (2006), 79(2), 402-8], Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome [ Am. J. Hum. Genet. (2006), 79(2), 402-8], odonto-onycho-dermal dysplasia [ Am. J. Hum. Genet. (2007), 81(4), 821-8], obesity [Diabetologia (2006), 49(4), 678-84], split-hand/foot malformation [Hum. Mol. Genet. (2008), 17(17), 2644-53], caudal duplication syndrome [ Am. J. Hum. Genet. (2006), 79(1), 155-62], tooth agenesis [ Am. J. Hum. Genet. (2004), 74(5), 1043-50], Wilms tumor [Science (2007), 315(5812), 642-5], skeletal dysplasia [ Nat. Genet. (2009), 41(1), 95-100], focal dermal hypoplasia [ Nat. Genet. (2007), 39(7), 836-8], autosomal recessive anonychia [ Nat. Genet. (2006), 38(11), 1245-7], neural tube defects [N. Engl. J. Med. (2007), 356(14), 1432-7], alpha-thalassemia (ATRX) syndrome [The Journal of Neuroscience (2008), 28(47), 12570 -12580], fragile X syndrome [PLoS Genetics (2010), 6(4), e1000898], ICF syndrome, Angelman syndrome [Brain Research Bulletin (2002), 57(1), 109-119], Prader-Willi syndrome [Journal of Neuroscience (2006), 26(20), 5383-5392], Beckwith-Wiedemann Syndrome [Pediatric and Developmental Pathology (2003), 6(4), 299-306] and Rett syndrome.
  • Regulation of cell signaling by the Wnt signaling pathway is critical for the formation of neuronal circuits. Wnt pathway modulates in neural tissue, among other things, axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnt pathway activates and/or regulates diverse signaling pathways and other processes that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link between neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been uncovered. Indeed, neuronal activity regulates the release of various Wnt proteins and the localization of their receptors. Wnt pathway mediates synaptic structural changes induced by neuronal activity or experience. Evidence suggests that dysfunction in Wnt signaling contributes to neurological disorders [ Brain Research Reviews (2000), 33(1), 1-12; Oncogene (2006) 25(57), 7545-7553; Molecular Neurodegeneration (2008), 3, 9; Neurobiology of Disease (2010), 38(2), 148-153; Journal of Neurodevelopmental Disorders (2011), 3(2), 162-174 and Cold Spring Harbor Perspectives in Biology February (2012), 4(2 )].
    • SUMMARY OF THE INVENTION
  • The present invention makes available methods and reagents, involving contacting a cell with an agent, such as a 1H-pyrazolo[3,4-b]pyridine compound, in a sufficient amount to antagonize Wnt activity, e. g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components.
  • Some embodiments disclosed herein include Wnt inhibitors containing a 1H-pyrazolo[3,4-b]pyridine core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.
  • One embodiment disclosed herein includes a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof:
    Figure imgb0001
  • In some embodiments of Formula (I):
    • R1 and R2 are independently selected from the group consisting of H, lower alkyl, halide, -(C1-9 alkyl)naryl(R6)q, -(C1-9 alkyl)nheteroaryl(R7)q, -(C1-9 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2, -OR10 and -NHC(=O)R11;
    • R3 is selected from the group consisting of H, halide and lower alkyl;
    • with the proviso that at least two of R1, R2 and R3 are H;
    • R4 and R5 are independently selected from the group consisting of H,-C(=O)N(R12)2, -aryl(R13)q, -heterocyclyl(R14)q, and -heteroaryl(R15)q;
    • with the proviso that at least one of R4 and R5 is H;
    • each R6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
    • each R7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
    • each R8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, -(C1-3 alkyl)naryl(R6)q, and -C1-4 alkyl;
    • each R9 is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl and -(C1-9 alkyl)N(R16)2;
    • alternatively, two adjacent R9 or two adjacent R12, may be taken together with the atoms to which they are attached to form a heterocyclyl(R17)q;
    • R10 is selected from the group consisting of H, -CF3, -(C1-3 alkyl)naryl(R6)q, and-C1-9 alkyl;
    • R11 is selected from the group consisting of -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl, -C1-9 alkyl and-CF3;
    • each R12 is independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q and -C1-9 alkyl;
    • each R13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, -CF3, CN, -(C1-3 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
    • each R14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3 and CN;
    • each R15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3, CN, -C(=O)(C1-3 alkyl), -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
    • each R16 is independently selected from the group consisting of H and lower alkyl;
    • each R17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q, and -C1-9 alkyl;
    • each R18 is a lower alkyl;
    • A is N or C;
    • with the proviso that if A is N then R2 is nil;
    • each q is an integer of 1 to 5;
    • each n is an integer of 0 or 1; and
    • with the proviso that Formula I is not a structure selected from the group consisting of:
    Figure imgb0002
    Figure imgb0003
    Figure imgb0004
    Figure imgb0005
    Figure imgb0006
    Figure imgb0007
    Figure imgb0008
    Figure imgb0009
    Figure imgb0010
    Figure imgb0011
    Figure imgb0012
    Figure imgb0013
    Figure imgb0014
    Figure imgb0015
  • Another embodiment disclosed herein includes a compound having the structure of Formula II or a pharmaceutically acceptable salt thereof:
    Figure imgb0016
  • In some embodiments of Formula (II):
    • R1 and R2 are independently selected from the group consisting of H, lower alkyl, halide, -(C1-9 alkyl)naryl(R6)q, -(C1-9 alkyl)nheteroaryl(R7)q, -(C1-9 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2, -OR10 and -NHC(=O)R11;
    • R3 is selected from the group consisting of H, halide and lower alkyl;
    • with the proviso that at least two of R1, R2 and R3 are H;
    • R4 and R5 are independently selected from the group consisting of H,-C(=O)N(R12)2, -aryl(R13)q, -heterocyclyl(R14)q, and -heteroaryl(R15)q;
    • with the proviso that at least one of R4 and R5 is H;
    • each R6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
    • each R7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
    • each R8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, -(C1-3 alkyl)naryl(R6)q, and -C1-4 alkyl;
    • each R9 is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3alkyl)naryl(R6)q, -(C1-3alkyl)ncarbocyclyl and -(C1-9alkyl)N(R16)2;
    • alternatively, two adjacent R9 or two adjacent R12, may be taken together with the atoms to which they are attached to form a heterocyclyl(R17)q;
    • R10 is selected from the group consisting of H, -CF3, -(C1-3 alkyl)naryl(R6)q, and-C1-9 alkyl;
    • R11 is selected from the group consisting of -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl, -C1-9 alkyl and-CF3;
    • each R12 is independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q and -C1-9 alkyl;
    • each R13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, -CF3, CN, -(C1-3 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
    • each R14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3 and CN;
    • each R15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3, CN, -C(=O)(C1-3 alkyl), -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
    • each R16 is independently selected from the group consisting of H and lower alkyl;
    • each R17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q, and -C1-9 alkyl;
    • each R18 is a lower alkyl;
    • A is N or C;
    • with the proviso that if A is N then R2 is nil;
    • each q is an integer of 1 to 5;
    • each n is an integer of 0 or 1; and
    • with the proviso that Formula II is not a structure selected from the group consisting of:
      Figure imgb0017
      Figure imgb0018
      Figure imgb0019
      Figure imgb0020
      Figure imgb0021
      Figure imgb0022
      Figure imgb0023
      Figure imgb0024
      Figure imgb0025
      Figure imgb0026
      Figure imgb0027
      Figure imgb0028
      Figure imgb0029
  • Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of general Formulas (I) or (II).
  • Some embodiments include pro-drugs of a compound of general Formulas (I) or (II).
  • Some embodiments of the present invention include pharmaceutical compositions comprising a compound of general Formulas (I) or (II) and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Other embodiments disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a subject affected by a disorder or disease in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, cell cycling and mutations in Wnt signaling components, a compound according to Formulas (I) or (II). Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct a genetic disorder due to mutations in Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary fibrosis, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-ameliasyndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
  • Another embodiment disclosed herein includes a pharmaceutical composition that has a compound according to any of the above formulas and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Some embodiments of the present invention include methods to prepare a compound of general Formulas (I) or (II).
  • It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
    • DETAILED DESCRIPTION OF THE INVENTION
  • Compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins would be of tremendous benefit. Certain embodiments provide such compositions and methods. Certain related compounds and methods are disclosed in U.S. Application Ser. No. 12/968,505, filed December 15, 2010 , which claims priority to U.S. Provisional Application Ser. No. 61/288,544 , all of which are incorporated by reference in their entirety herein.
  • Some embodiments relate to a method for treating a disease including, but not limited to, cancers, diabetic retinopathy, idiopathic pulmonary fibrosis, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Müllerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
  • In some embodiments, pharmaceutical compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by the pathological activation or mutations of the Wnt pathway. The composition includes a pharmaceutically acceptable carrier and a Wnt pathway inhibitor as described herein.
    • Definitions
  • Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
  • In this specification and in the claims, the following terms have the meanings as defined. As used herein, "alkyl" means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl and sec-pentyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, thio, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, heterocyclyl, carbocyclyl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (e.g., containing - C=C- or -C≡C- subunits), at one or several positions. Typically, alkyl groups will comprise 1 to 9 carbon atoms, preferably 1 to 6, more preferably 1 to 4, and most preferably 1 to 2 carbon atoms.
  • As used herein, "carbocyclyl" means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents, e.g., alkyl, halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms, preferably 3 to 6.
  • As used herein, "lower alkyl" means a subset of alkyl, and thus is a hydrocarbon substituent, which is linear or branched. Preferred lower alkyls are of 1 to about 3 carbons, and may be branched or linear. Examples of lower alkyl include n-propyl, isopropyl, ethyl, and methyl. Likewise, radicals using the terminology "lower" refer to radicals preferably with 1 to about 3 carbons in the alkyl portion of the radical.
  • As used herein, "amido" means a H-CON- or alkyl-CON-, carbocyclyl-CON-, aryl-CON-, heteroaryl-CON- or heterocyclyl-CON group wherein the alkyl, carbocyclyl, heteroaryl, aryl or heterocyclyl group is as herein described.
  • As used herein, "aryl" means an aromatic radical having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) with only carbon atoms present in the ring backbone. Aryl groups can either be unsubstituted or substituted with one or more substituents, e.g., alkyl, amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents. A preferred carbocyclic aryl is phenyl.
  • As used herein, the term "heteroaryl" means an aromatic radical having one or more heteroatom(s) (e.g., N, O, or S) in the ring backbone and may include a single ring (e.g., pyridine) or multiple condensed rings (e.g., quinoline). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents, e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, and others.
  • In these definitions it is clearly contemplated that substitution on the aryl and heteroaryl rings is within the scope of certain embodiments. Where substitution occurs, the radical is called substituted aryl or substituted heteroaryl. Preferably one to three and more preferably one or two substituents occur on the aryl or heteroaryl ring. Though many substituents will be useful, preferred substituents include those commonly found in aryl or heteroaryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, mercapto and the like.
  • As used herein, "amide" includes both RNR'CO- and RCONR'-. R can be substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted carbocyclyl. R' can be H or substituted or unsubstituted alkyl.
  • As used herein, "halo", "halide" or "halogen" is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. Most preferred halide is fluorine.
  • As used herein, "haloalkyl" means a hydrocarbon substituent, which is linear or branched or cyclic alkyl, alkenyl or alkynyl substituted with chloro, bromo, fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbons in length, more preferred haloalkyls are 1 to about 2 carbons, and most preferred are 1 carbon in length. The skilled artisan will recognize then that as used herein, "haloalkylene" means a diradical variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another functional group.
  • As used herein, "heterocyclyl" means a cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple fused rings. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Heterocyclyls may be substituted or unsubstituted with one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, and other substituents, and are attached to other groups via any available valence, preferably any available carbon or nitrogen. More preferred heterocycles are of 5-7 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one up to three of O, N or S, and wherein when the heterocycle is five membered, preferably it has one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.
  • As used herein, "substituted amino" means an amino radical which is substituted by one or two alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groups, wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.
  • As used herein, "sulfonamido" means an alkyl-S(O)2N-, aryl-S(O)2N-, heteroaryl-S(O)2N-, carbocyclyl-S(O)2N- or heterocyclyl-S(O)2N- group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described.
  • As used herein, when two groups are indicated to be "linked" or "bonded" to form a "ring," it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions, and it is within the purview of the skilled artisan to both envision such rings and the methods of their formations. Preferred are rings having from 3-7 members, more preferably 5 or 6 members. As used herein the term "ring" or "rings" when formed by the combination of two radicals refers to heterocyclic, carbocyclic, aryl, or heteroaryl rings.
  • The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures are only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this invention, though such resonance forms or tautomers are not represented herein.
  • The compounds provided herein may encompass various stereochemical forms. The compounds also encompasses diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
  • The term "administration" or "administering" refers to a method of giving a dosage of a compound or pharmaceutical composition comprising the same to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease.
  • A "diagnostic" as used herein is a compound, method, system, or device that assists in the identification and characterization of a health or disease state. The diagnostic can be used in standard assays as is known in the art.
  • The term "mammal" is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, dogs, and cats, but also includes many other species.
  • The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies .
  • The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297 .
  • "Solvate" refers to the compound formed by the interaction of a solvent and a Wnt pathway inhibitor, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
  • "Subject" as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • By "therapeutically effective amount" or "pharmaceutically effective amount" of a compound as provided herein is one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. "Therapeutically effective amount" is also intended to include one or more of the compounds of Formula (I) in combination with one or more other agents that are effective to inhibit Wnt related diseases and/or conditions. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou, Cancer Research (2010), 70(2), 440-446, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient's height, weight, sex, age and medical history.
  • A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease, and includes curing a disease. "Curing" means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).
  • "Treat," "treatment," or "treating," as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder and/or reducing the severity of symptoms that will or are expected to develop.
  • "Drug-eluting" and or controlled release as used herein refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug-eluting material pass therefrom over time into the surrounding body tissue.
  • "Drug-eluting material" and or controlled release material as used herein refers to any natural, synthetic or semi-synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time.
  • "Elutable drug" as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body.
    • Compounds
  • The compounds and compositions described herein can be used as anti-proliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and/or as inhibitors of the Wnt signaling pathway, e.g., for treating diseases or disorders associated with aberrant Wnt signaling. In addition, the compounds can be used as inhibitors of one or more kinases, kinase receptors, or kinase complexes. Such compounds and compositions are also useful for controlling cellular proliferation, differentiation, and/or apoptosis.
  • Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or pro-drugs thereof of Formula (I):
    Figure imgb0030
  • In some embodiments of Formula I, R1 and R2 are independently selected from the group consisting of H, lower alkyl, halide, -(C1-9 alkyl)naryl(R6)q, -(C1-9 alkyl)nheteroaryl(R7)q, -(C1-9 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2, -OR10 and-NHC(=O)R11.
  • In some embodiments of Formula I, R3 is selected from the group consisting of H, halide and lower alkyl.
  • In some embodiments of Formula I, there is the proviso that at least two of R1, R2 and R3 are H.
  • In some embodiments of Formula I, R4 and R5 are independently selected from the group consisting of H, -C(=O)N(R12)2, -aryl(R13)q, -heterocyclyl(R14)q, and -heteroaryl(R15)q with the proviso that either R3 or R4 is H but not both.
  • In some embodiments of Formula I, each R6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN.
  • In some embodiments of Formula I, each R7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN.
  • In some embodiments of Formula I, R8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, -(C1-3alkyl)narylR6, and -C1-4 alkyl.
  • In some embodiments of Formula I, each R9 is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl and -(C1-9 alkyl)N(R16)2.
  • In some embodiments of Formula I, two adjacent R9 or two adjacent R12, may be taken together with the atoms to which they are attached to form a heterocyclyl(R17)q.
  • In some embodiments, R10 is selected from the group consisting of H, -CF3, -(C1-3 alkyl)naryl(R6)q, and -C1-9 alkyl.
  • In some embodiments of Formula I, R11 is selected from the group consisting of -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl, -C1-9 alkyl and -CF3.
  • In some embodiments of Formula I, each R12 is independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q and -C1-9 alkyl.
  • In some embodiments of Formula I, each R13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, -CF3, CN, -(C1-3 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18.
  • In some embodiments of Formula I, each R14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3 and CN.
  • In some embodiments of Formula I, each R15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3, CN, -C(=O)(C1-3 alkyl), -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18.
  • In some embodiments of Formula I, each R16 is independently selected from the group consisting of H and lower alkyl.
  • In some embodiments of Formula I, each R17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q, and -C1-9 alkyl.
  • In some embodiments of Formula I, each R18 is a lower alkyl.
  • In some embodiments of Formula I, A is N or C.
  • In some embodiments of Formula I, there is the proviso that if A is N then R2 is nil;
  • In some embodiments of Formula I, each q is an integer of 1 to 5.
  • In some embodiments of Formula I, each n is an integer of 0 or 1.
  • In some embodiments, there is the proviso that Formula I is not a structure selected from the group consisting of:
    Figure imgb0031
    Figure imgb0032
    Figure imgb0033
    Figure imgb0034
    Figure imgb0035
    Figure imgb0036
    Figure imgb0037
    Figure imgb0038
    Figure imgb0039
    Figure imgb0040
    Figure imgb0041
    Figure imgb0042
    Figure imgb0043
    Figure imgb0044
  • In some embodiments of either Formula I, A is C.
  • In some embodiments of Formula I, A is N and R2 is nil.
  • In some embodiments of Formula I, A is N; and R1 and R3 are both H.
  • In some embodiments of Formula I, aryl is phenyl.
  • In some embodiments of Formula I, heteroaryl is pyridinyl.
  • In some embodiments of Formula I, heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
  • In some embodiments of Formula I, R2 is selected from the group consisting of H, -(C1-9 alkyl)nheterocyclyl(R8)q, -NHC(=O)R11 and -(C1-9 alkyl)nN(R9)2 and R1 and R3 are both H.
  • In some embodiments of Formula I, R2 is -CH2N(R9)2 or -N(R9)2.
  • In some embodiments of Formula I, R9 is independently selected from the group consisting of H, Me, Et, -CH2phenyl and -CH2carbocyclyl.
  • In some embodiments of Formula I, R2 is -NHC(=O)R11.
  • In some embodiments of Formula I, R11 is selected from the group consisting of -C1-5 alkyl, carbocyclyl, phenyl(R6)q, and -CH2phenyl(R6)q.
  • In some embodiments of Formula I, R4 is phenyl(R13)q.
  • In some embodiments of Formula I, R4 is -heterocyclyl(R14)q.
  • In some embodiments of Formula I, R4 is -heteroaryl(R15)q.
  • In some embodiments of Formula I, R13 is one substituent attached to the phenyl comprising a fluorine atom.
  • In some embodiments of Formula I, R13 is two substituents each attached to the phenyl comprising a fluorine atom and either a -(CH2)nN(R5)2 or a-(CH2)nNHSO2R18.
  • In some embodiments of Formula I, the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; and the R14 is H or Me.
  • In some embodiments of Formula I, the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; and R15 is lower alkyl or halide.
  • Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or pro-drugs thereof of Formula (II):
    Figure imgb0045
  • In some embodiments of Formula II, R1 and R2 are independently selected from the group consisting of H, lower alkyl, halide, -(C1-9 alkyl)naryl(R6)q, -(C1-9 alkyl)nheteroaryl(R7)q, -(C1-9 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2, -OR10 and-NHC(=O)R11.
  • In some embodiments of Formula II, R3 is selected from the group consisting of H, halide and lower alkyl.
  • In some embodiments of Formula II, there is the proviso that at least two of R1, R2 and R3 are H.
  • In some embodiments of Formula II, there is the proviso that if A is N then R2 is nil.
  • In some embodiments of Formula II, R4 and R5 are independently selected from the group consisting of H, -C(=O)N(R12)2, -aryl(R13)q, -heterocyclyl(R14)q, and -heteroaryl(R15)q with the proviso that either R3 or R4 is H but not both.
  • In some embodiments of Formula II, each R6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN.
  • In some embodiments of Formula II, each R7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN.
  • In some embodiments of Formula II, each R8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, -(C1-3 alkyl)naryl(R6)q, and -C1-4 alkyl.
  • In some embodiments of Formula II, each R9 is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl and -(C1-9 alkyl)N(R16)2.
  • In some embodiments of Formula II, two adjacent R9 or two adjacent R12, may be taken together with the atoms to which they are attached to form a heterocyclyl(R17)q.
  • In some embodiments of Formula II, R10 is selected from the group consisting of H, -CF3, -(C1-3 alkyl)naryl(R6)q, and -C1-9 alkyl.
  • In some embodiments of Formula II, R11 is selected from the group consisting of -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl, -C1-9 alkyl and -CF3.
  • In some embodiments of Formula II, each R12 is independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q and -C1-9 alkyl.
  • In some embodiments of Formula II, each R13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, -CF3, CN, -(C1-3 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18.
  • In some embodiments of Formula II, each R14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3 and CN.
  • In some embodiments of Formula II, each R15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3, CN, -C(=O)(C1-3 alkyl), -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18.
  • In some embodiments of Formula II, each R16 is independently selected from the group consisting of H and lower alkyl.
  • In some embodiments of Formula II, each R17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q, and -C1-9 alkyl.
  • In some embodiments of Formula II, each R18 is a lower alkyl.
  • In some embodiments of Formula II, A is N or C.
  • In some embodiments of Formula II, there is the proviso that if A is N then R2 is nil;
  • In some embodiments of Formula II, each q is an integer of 1 to 5.
  • In some embodiments of Formula II, each n is an integer of 0 or 1.
  • In some embodiments, Formula II is not a structure selected from the group consisting of:
    Figure imgb0046
    Figure imgb0047
    Figure imgb0048
    Figure imgb0049
    Figure imgb0050
    Figure imgb0051
    Figure imgb0052
    Figure imgb0053
    Figure imgb0054
    Figure imgb0055
    Figure imgb0056
    Figure imgb0057
    Figure imgb0058
  • In some embodiments of Formula II, A is C.
  • In some embodiments of Formula II, A is N and R2 is nil.
  • In some embodiments of Formula II, A is N; and R1 and R3 are both H.
  • In some embodiments of Formula II, aryl is phenyl.
  • In some embodiments of Formula II, heteroaryl is pyridinyl.
  • In some embodiments of Formula II, heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
  • In some embodiments of Formula II, R2 is selected from the group consisting of H, -(C1-9 alkyl)nheterocyclyl(R8)q, -NHC(=O)R11 and -(C1-9 alkyl)nN(R9)2 and R1 and R3 are both H.
  • In some embodiments of Formula II, R2 is -CH2N(R9)2 or -N(R9)2.
  • In some embodiments of Formula II, R9 is independently selected from the group consisting of H, Me, Et, -CH2phenyl and -CH2carbocyclyl.
  • In some embodiments of Formula II, R2 is -NHC(=O)R11.
  • In some embodiments of Formula II, R11 is selected from the group consisting of -C1-5 alkyl, carbocyclyl, phenyl(R6)2, and -CH2phenyl(R6)q.
  • In some embodiments of Formula II, R4 is phenyl(R13)q.
  • In some embodiments of Formula II, R4 is -heterocyclyl(R14)q.
  • In some embodiments of Formula II, R4 is -heteroaryl(R15)q.
  • In some embodiments of Formula II, R13 is one substituent attached to the phenyl comprising a fluorine atom.
  • In some embodiments of Formula II, R13 is two substituents each attached to the phenyl comprising a fluorine atom and either a -(CH2)nN(R5)2 or a-(CH2)nNHSO2R18.
  • In some embodiments of Formula II, the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; and the R14 is H or Me.
  • In some embodiments of Formula II, the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; and R15 is lower alkyl or halide.
  • In some embodiments of either Formula I or II, R3 is lower alkyl; and R1 and R2 are both H.
  • In some embodiments of either Formula I or II, R2 is -NHC(=O)(C1-2 alkyl).
  • In some embodiments of either Formula I or II, R2 is -NHC(=O)(C1-3 alkyl).
  • In some embodiments of either Formula I or II, R2 is -NHC(=O)(C1-4 alkyl).
  • In some embodiments of either Formula I or II, R2 is -NHC(=O)(C1-5 alkyl).
  • In some embodiments of either Formula I or II, R2 is-NHC(=O)carbocyclyl.
  • In some embodiments of either Formula I or II, R2 is
    Figure imgb0059
  • In some embodiments of either Formula I or II, R2 is -NH(C1-3 alkyl).
  • In some embodiments of either Formula I or II, R2 is -N(C1-3 alkyl)2.
  • In some embodiments of either Formula I or II, R2 is -NH2.
  • In some embodiments of either Formula I or II, R4 is pyridinyl.
  • In some embodiments of either Formula I or II, R4 is furyl.
  • In some embodiments of either Formula I or II, R4 is thiophenyl.
  • In some embodiments of either Formula I or II, R4 is imidazolyl.
  • In some embodiments of either Formula I or II, R4 is piperazinyl
  • In some embodiments of either Formula I or II, R4 is piperidinyl.
  • In some embodiments of either Formula I or II, R4 is 1-methylpiperazinyl.
  • In some embodiments of either Formula I or II, R4 is selected from the group consisting of:
    Figure imgb0060
     and
    Figure imgb0061
  • In some embodiments of either Formula I or II, R11 is cyclopropyl.
  • In some embodiments of either Formula I or II, R11 is cyclobutyl.
  • In some embodiments of either Formula I or II, R11 is cyclopentyl.
  • In some embodiments of either Formula I or II, R11 is cyclohexyl.
  • In some embodiments of either Formula I or II, R13 is 1-2 fluorine atoms.
  • In some embodiments of either Formula I or II, R13 is -(C1-6 alkyl)NHSO2R11.
  • In some embodiments of either Formula I or II, R13 is -(C1-4 alkyl)NHSO2R11.
  • In some embodiments of either Formula I or II, R13 is -(C1-2 alkyl)NHSO2R11.
  • In some embodiments of either Formula I or II, R13 is-CH22NHSO2R11.
  • In some embodiments of either Formula I or II, R13 is-CH2NHSO2CH3.
  • In some embodiments of either Formula I or II, R13 is -NR12(C1-6 alkyl)NR11R12.
  • In some embodiments of either Formula I or II, R13 is -NR12(C1-4 alkyl)NR11R12.
  • In some embodiments of either Formula I or II, R13 is - NR12CH2CH2NR11R12.
  • In some embodiments of either Formula I or II, R13 is-NHCH2CH2NR11R12.
  • In some embodiments of either Formula I or II, R13 is-NHCH2CH2N(CH3)2.
  • In some embodiments of either Formula I or II, R13 is 2 substituents consisting of 1 fluorine atom and -NR12(C1-6 alkyl)NR11R12.
  • In some embodiments of either Formula I or II, R13 is 2 substituents consisting of 1 fluorine atom and -NHCH2CH2NR11R12,
  • In some embodiments of either Formula I or II, R13 is 2 substituents consisting of 1 fluorine atom and -(C1-6 alkyl)NHSO2R11.
  • In some embodiments of either Formula I or II, R13 is 2 substituents consisting of 1 fluorine atom and -CH2NHSO2R11.
  • In some embodiments of either Formula I or II, R15 is Me.
  • In some embodiments of either Formula I or II, R15 is halide.
  • In some embodiments of either Formula I or II, R15 is fluorine.
  • In some embodiments of either Formula I or II, R15 is -C(=O)(C1-3 alkyl).
  • In some embodiments of either Formula I or II, q is an integer ranging from 1 to 5, preferably 1 or 3, more preferably 1-2.
  • In some embodiments of either Formula I or II, A is C; R1, R2 and R3 are all H; R4 is selected from the group consisting of pyridine and -heterocyclyl(R14)q; q is 1 or 2 and R14 is selected from the group consisting of H, F and -(C1-4 alkyl).
  • In some embodiments of either Formula I or II, A is C; R1 and R3 are H; R2 is amino; R4 is selected from the group consisting of -phenyl(R13)q and-heterocyclyl(R14)q, -heteroaryl(R15)q; q is 1 or 2; R15 is H; R14 is selected from the group consisting of H, F and -(C1-4 alkyl); R13 is 1-2 fluorine atoms; and the heteroaryl is selected from the group consisting of pyridine, furan and thiophene.
  • In some embodiments of either Formula I or II, A is C; R1 and R3 are H; R2 is -NHC(=O)R11; R11 is selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl; R4 is selected from the group consisting of H, -heteroaryl(R15)q,-phenyl(R13)q and -heterocyclyl(R14)q; q is 1 or 2; R15 is H or F; R14 is selected from the group consisting of H, F and -(C1-4 alkyl); R13 is selected from the group consisting of 1-2 fluorine atoms and -CH2NHSO2R18; and the heteroaryl is selected from the group consisting of pyridine, furan and thiophene.
  • In some embodiments of either Formula I or II, A is C; R1 and R3 are H; R2 is -CH2N(R9)2; R4 is selected from the group consisting of H, -heteroaryl(R15)q,-phenyl(R13)q and -heterocyclyl(R14)q; q is 1 or 2; R15 is selected from the group consisting of H, F, Me and -C(=O)Me; R14 is selected from the group consisting of H, F and -(C1-4 alkyl); R13 is 1-2 fluorine atoms; the two R9 are linked to form a five-membered heterocyclyl ring; the heterocyclyl ring is substituted with 1-2 fluorine atoms; and the heteroaryl is selected from the group consisting of pyridine, furan and thiophene.
  • Pharmaceutically acceptable salts of all of the above embodiments are also contemplated.
  • Illustrative compounds of Formulas (I) and (II) are shown in Table 1. Table 1.
    1
    Figure imgb0062
         		2
    Figure imgb0063
         		3
    Figure imgb0064
    4
    Figure imgb0065
         		5
    Figure imgb0066
         		6
    Figure imgb0067
    7
    Figure imgb0068
         		8
    Figure imgb0069
         		9
    Figure imgb0070
    10
    Figure imgb0071
         		11
    Figure imgb0072
         		12
    Figure imgb0073
    13
    Figure imgb0074
         		14
    Figure imgb0075
         		15
    Figure imgb0076
    16
    Figure imgb0077
         		17
    Figure imgb0078
         		18
    Figure imgb0079
    19
    Figure imgb0080
         		20
    Figure imgb0081
         		21
    Figure imgb0082
    22
    Figure imgb0083
         		23
    Figure imgb0084
         		24
    Figure imgb0085
    25
    Figure imgb0086
         		26
    Figure imgb0087
         		27
    Figure imgb0088
    28
    Figure imgb0089
         		29
    Figure imgb0090
         		30
    Figure imgb0091
    31
    Figure imgb0092
         		32
    Figure imgb0093
         		33
    Figure imgb0094
    34
    Figure imgb0095
         		35
    Figure imgb0096
         		36
    Figure imgb0097
    37
    Figure imgb0098
         		38
    Figure imgb0099
         		39
    Figure imgb0100
    40
    Figure imgb0101
         		41
    Figure imgb0102
         		42
    Figure imgb0103
    43
    Figure imgb0104
         		44
    Figure imgb0105
         		45
    Figure imgb0106
    46
    Figure imgb0107
         		47
    Figure imgb0108
         		48
    Figure imgb0109
    49
    Figure imgb0110
         		50
    Figure imgb0111
         		51
    Figure imgb0112
    52
    Figure imgb0113
         		53
    Figure imgb0114
         		54
    Figure imgb0115
    55
    Figure imgb0116
         		56
    Figure imgb0117
         		57
    Figure imgb0118
    58
    Figure imgb0119
         		59
    Figure imgb0120
         		60
    Figure imgb0121
    61
    Figure imgb0122
         		62
    Figure imgb0123
         		63
    Figure imgb0124
    64
    Figure imgb0125
         		65
    Figure imgb0126
         		66
    Figure imgb0127
    67
    Figure imgb0128
         		68
    Figure imgb0129
         		69
    Figure imgb0130
    70
    Figure imgb0131
         		71
    Figure imgb0132
         		72
    Figure imgb0133
    73
    Figure imgb0134
         		74
    Figure imgb0135
         		75
    Figure imgb0136
    76
    Figure imgb0137
         		77
    Figure imgb0138
         		78
    Figure imgb0139
    79
    Figure imgb0140
         		80
    Figure imgb0141
         		81
    Figure imgb0142
    82
    Figure imgb0143
         		83
    Figure imgb0144
         		84
    Figure imgb0145
    85
    Figure imgb0146
         		86
    Figure imgb0147
         		87
    Figure imgb0148
    88
    Figure imgb0149
         		89
    Figure imgb0150
         		90
    Figure imgb0151
    91
    Figure imgb0152
         		92
    Figure imgb0153
         		93
    Figure imgb0154
    94
    Figure imgb0155
         		95
    Figure imgb0156
         		96
    Figure imgb0157
    97
    Figure imgb0158
         		98
    Figure imgb0159
         		99
    Figure imgb0160
    100
    Figure imgb0161
         		101
    Figure imgb0162
         		102
    Figure imgb0163
    103
    Figure imgb0164
         		104
    Figure imgb0165
         		105
    Figure imgb0166
    106
    Figure imgb0167
         		107
    Figure imgb0168
         		108
    Figure imgb0169
    109
    Figure imgb0170
         		110
    Figure imgb0171
         		111
    Figure imgb0172
    112
    Figure imgb0173
         		113
    Figure imgb0174
         		114
    Figure imgb0175
    115
    Figure imgb0176
         		116
    Figure imgb0177
         		117
    Figure imgb0178
    118
    Figure imgb0179
         		119
    Figure imgb0180
         		120
    Figure imgb0181
    121
    Figure imgb0182
         		122
    Figure imgb0183
         		123
    Figure imgb0184
    124
    Figure imgb0185
         		125
    Figure imgb0186
         		126
    Figure imgb0187
    127
    Figure imgb0188
         		128
    Figure imgb0189
         		129
    Figure imgb0190
    130
    Figure imgb0191
         		131
    Figure imgb0192
         		132
    Figure imgb0193
    133
    Figure imgb0194
         		134
    Figure imgb0195
         		135
    Figure imgb0196
    136
    Figure imgb0197
         		137
    Figure imgb0198
         		138
    Figure imgb0199
    139
    Figure imgb0200
         		140
    Figure imgb0201
         		141
    Figure imgb0202
    142
    Figure imgb0203
         		143
    Figure imgb0204
         		144
    Figure imgb0205
    145
    Figure imgb0206
         		146
    Figure imgb0207
         		147
    Figure imgb0208
    148
    Figure imgb0209
         		149
    Figure imgb0210
         		150
    Figure imgb0211
    151
    Figure imgb0212
         		152
    Figure imgb0213
         		153
    Figure imgb0214
    154
    Figure imgb0215
         		155
    Figure imgb0216
         		156
    Figure imgb0217
    157
    Figure imgb0218
         		158
    Figure imgb0219
         		159
    Figure imgb0220
    160
    Figure imgb0221
         		161
    Figure imgb0222
         		162
    Figure imgb0223
    163
    Figure imgb0224
         		164
    Figure imgb0225
         		165
    Figure imgb0226
    166
    Figure imgb0227
         		167
    Figure imgb0228
         		168
    Figure imgb0229
    169
    Figure imgb0230
         		170
    Figure imgb0231
         		171
    Figure imgb0232
    172
    Figure imgb0233
         		173
    Figure imgb0234
         		174
    Figure imgb0235
    175
    Figure imgb0236
         		176
    Figure imgb0237
         		177
    Figure imgb0238
    178
    Figure imgb0239
         		179
    Figure imgb0240
         		180
    Figure imgb0241
    181
    Figure imgb0242
         		182
    Figure imgb0243
         		183
    Figure imgb0244
    184
    Figure imgb0245
         		185
    Figure imgb0246
         		186
    Figure imgb0247
    187
    Figure imgb0248
         		188
    Figure imgb0249
         		189
    Figure imgb0250
    190
    Figure imgb0251
         		191
    Figure imgb0252
         		192
    Figure imgb0253
    193
    Figure imgb0254
         		194
    Figure imgb0255
         		195
    Figure imgb0256
    196
    Figure imgb0257
         		197
    Figure imgb0258
         		198
    Figure imgb0259
    199
    Figure imgb0260
         		200
    Figure imgb0261
         		201
    Figure imgb0262
    202
    Figure imgb0263
         		203
    Figure imgb0264
         		204
    Figure imgb0265
    205
    Figure imgb0266
         		206
    Figure imgb0267
         		207
    Figure imgb0268
    208
    Figure imgb0269
         		209
    Figure imgb0270
         		210
    Figure imgb0271
    211
    Figure imgb0272
         		212
    Figure imgb0273
         		213
    Figure imgb0274
    214
    Figure imgb0275
         		215
    Figure imgb0276
         		216
    Figure imgb0277
    217
    Figure imgb0278
         		218
    Figure imgb0279
         		219
    Figure imgb0280
    220
    Figure imgb0281
         		221
    Figure imgb0282
         		222
    Figure imgb0283
    223
    Figure imgb0284
         		224
    Figure imgb0285
         		225
    Figure imgb0286
    226
    Figure imgb0287
         		227
    Figure imgb0288
         		228
    Figure imgb0289
    229
    Figure imgb0290
         		230
    Figure imgb0291
         		231
    Figure imgb0292
    232
    Figure imgb0293
         		233
    Figure imgb0294
         		234
    Figure imgb0295
    235
    Figure imgb0296
         		236
    Figure imgb0297
         		237
    Figure imgb0298
    238
    Figure imgb0299
         		239
    Figure imgb0300
         		240
    Figure imgb0301
    241
    Figure imgb0302
         		242
    Figure imgb0303
         		243
    Figure imgb0304
    244
    Figure imgb0305
         		245
    Figure imgb0306
         		246
    Figure imgb0307
    247
    Figure imgb0308
         		248
    Figure imgb0309
         		249
    Figure imgb0310
    250
    Figure imgb0311
         		251
    Figure imgb0312
         		252
    Figure imgb0313
    253
    Figure imgb0314
         		254
    Figure imgb0315
         		255
    Figure imgb0316
    256
    Figure imgb0317
         		257
    Figure imgb0318
         		258
    Figure imgb0319
    259
    Figure imgb0320
         		260
    Figure imgb0321
         		261
    Figure imgb0322
    262
    Figure imgb0323
         		263
    Figure imgb0324
         		264
    Figure imgb0325
    265
    Figure imgb0326
         		266
    Figure imgb0327
         		267
    Figure imgb0328
    268
    Figure imgb0329
         		269
    Figure imgb0330
         		270
    Figure imgb0331
    271
    Figure imgb0332
         		272
    Figure imgb0333
         		273
    Figure imgb0334
    274
    Figure imgb0335
         		275
    Figure imgb0336
         		276
    Figure imgb0337
    277
    Figure imgb0338
         		278
    Figure imgb0339
         		279
    Figure imgb0340
    280
    Figure imgb0341
         		281
    Figure imgb0342
         		282
    Figure imgb0343
    283
    Figure imgb0344
         		284
    Figure imgb0345
         		285
    Figure imgb0346
    286
    Figure imgb0347
         		287
    Figure imgb0348
         		288
    Figure imgb0349
    289
    Figure imgb0350
         		290
    Figure imgb0351
         		291
    Figure imgb0352
    292
    Figure imgb0353
         		293
    Figure imgb0354
         		294
    Figure imgb0355
    295
    Figure imgb0356
         		296
    Figure imgb0357
         		297
    Figure imgb0358
    298
    Figure imgb0359
         		299
    Figure imgb0360
         		300
    Figure imgb0361
    301
    Figure imgb0362
         		302
    Figure imgb0363
         		303
    Figure imgb0364
    304
    Figure imgb0365
         		305
    Figure imgb0366
         		306
    Figure imgb0367
    307
    Figure imgb0368
         		308
    Figure imgb0369
         		309
    Figure imgb0370
    310
    Figure imgb0371
         		311
    Figure imgb0372
         		312
    Figure imgb0373
    313
    Figure imgb0374
         		314
    Figure imgb0375
         		315
    Figure imgb0376
    316
    Figure imgb0377
         		317
    Figure imgb0378
         		318
    Figure imgb0379
    319
    Figure imgb0380
         		320
    Figure imgb0381
         		321
    Figure imgb0382
    322
    Figure imgb0383
         		323
    Figure imgb0384
         		324
    Figure imgb0385
    325
    Figure imgb0386
         		326
    Figure imgb0387
         		327
    Figure imgb0388
    328
    Figure imgb0389
         		329
    Figure imgb0390
         		330
    Figure imgb0391
    331
    Figure imgb0392
         		332
    Figure imgb0393
         		333
    Figure imgb0394
    334
    Figure imgb0395
         		335
    Figure imgb0396
         		336
    Figure imgb0397
    337
    Figure imgb0398
         		338
    Figure imgb0399
         		339
    Figure imgb0400
    340
    Figure imgb0401
         		341
    Figure imgb0402
         		342
    Figure imgb0403
    343
    Figure imgb0404
         		344
    Figure imgb0405
         		345
    Figure imgb0406
    346
    Figure imgb0407
         		347
    Figure imgb0408
         		348
    Figure imgb0409
    349
    Figure imgb0410
         		350
    Figure imgb0411
         		351
    Figure imgb0412
    352
    Figure imgb0413
         		353
    Figure imgb0414
         		354
    Figure imgb0415
    355
    Figure imgb0416
         		356
    Figure imgb0417
         		357
    Figure imgb0418
    358
    Figure imgb0419
         		359
    Figure imgb0420
         		360
    Figure imgb0421
    361
    Figure imgb0422
         		362
    Figure imgb0423
         		363
    Figure imgb0424
    364
    Figure imgb0425
         		365
    Figure imgb0426
         		366
    Figure imgb0427
    367
    Figure imgb0428
         		368
    Figure imgb0429
         		369
    Figure imgb0430
    370
    Figure imgb0431
         		371
    Figure imgb0432
         		372
    Figure imgb0433
    373
    Figure imgb0434
         		374
    Figure imgb0435
         		375
    Figure imgb0436
    376
    Figure imgb0437
         		377
    Figure imgb0438
         		378
    Figure imgb0439
    379
    Figure imgb0440
         		380
    Figure imgb0441
         		381
    Figure imgb0442
    382
    Figure imgb0443
         		383
    Figure imgb0444
         		384
    Figure imgb0445
    385
    Figure imgb0446
         		386
    Figure imgb0447
         		387
    Figure imgb0448
    388
    Figure imgb0449
         		389
    Figure imgb0450
         		390
    Figure imgb0451
    391
    Figure imgb0452
         		392
    Figure imgb0453
         		393
    Figure imgb0454
    394
    Figure imgb0455
         		395
    Figure imgb0456
         		396
    Figure imgb0457
    397
    Figure imgb0458
         		398
    Figure imgb0459
         		399
    Figure imgb0460
    400
    Figure imgb0461
         		401
    Figure imgb0462
         		402
    Figure imgb0463
    403
    Figure imgb0464
         		404
    Figure imgb0465
         		405
    Figure imgb0466
    406
    Figure imgb0467
         		407
    Figure imgb0468
         		408
    Figure imgb0469
    409
    Figure imgb0470
         		410
    Figure imgb0471
         		411
    Figure imgb0472
    412
    Figure imgb0473
         		413
    Figure imgb0474
         		414
    Figure imgb0475
    415
    Figure imgb0476
         		416
    Figure imgb0477
         		417
    Figure imgb0478
    418
    Figure imgb0479
         		419
    Figure imgb0480
         		420
    Figure imgb0481
    421
    Figure imgb0482
         		422
    Figure imgb0483
         		423
    Figure imgb0484
    424
    Figure imgb0485
         		425
    Figure imgb0486
         		426
    Figure imgb0487
    427
    Figure imgb0488
         		428
    Figure imgb0489
         		429
    Figure imgb0490
    430
    Figure imgb0491
         		431
    Figure imgb0492
         		432
    Figure imgb0493
    433
    Figure imgb0494
         		434
    Figure imgb0495
         		435
    Figure imgb0496
    436
    Figure imgb0497
         		437
    Figure imgb0498
         		438
    Figure imgb0499
    439
    Figure imgb0500
         		440
    Figure imgb0501
         		441
    Figure imgb0502
    442
    Figure imgb0503
         		443
    Figure imgb0504
         		444
    Figure imgb0505
    445
    Figure imgb0506
         		446
    Figure imgb0507
         		447
    Figure imgb0508
    448
    Figure imgb0509
         		449
    Figure imgb0510
         		450
    Figure imgb0511
    451
    Figure imgb0512
         		452
    Figure imgb0513
         		453
    Figure imgb0514
    454
    Figure imgb0515
         		455
    Figure imgb0516
         		456
    Figure imgb0517
    457
    Figure imgb0518
         		458
    Figure imgb0519
         		459
    Figure imgb0520
    460
    Figure imgb0521
         		461
    Figure imgb0522
         		462
    Figure imgb0523
    463
    Figure imgb0524
         		464
    Figure imgb0525
         		465
    Figure imgb0526
    466
    Figure imgb0527
         		467
    Figure imgb0528
         		468
    Figure imgb0529
    469
    Figure imgb0530
         		470
    Figure imgb0531
         		471
    Figure imgb0532
    472
    Figure imgb0533
         		473
    Figure imgb0534
         		474
    Figure imgb0535
    475
    Figure imgb0536
         		476
    Figure imgb0537
         		477
    Figure imgb0538
    478
    Figure imgb0539
         		479
    Figure imgb0540
         		480
    Figure imgb0541
    481
    Figure imgb0542
         		482
    Figure imgb0543
         		483
    Figure imgb0544
    484
    Figure imgb0545
         		485
    Figure imgb0546
         		486
    Figure imgb0547
    487
    Figure imgb0548
         		488
    Figure imgb0549
         		489
    Figure imgb0550
    490
    Figure imgb0551
         		491
    Figure imgb0552
         		492
    Figure imgb0553
    493
    Figure imgb0554
         		494
    Figure imgb0555
         		495
    Figure imgb0556
    496
    Figure imgb0557
         		497
    Figure imgb0558
         		498
    Figure imgb0559
    499
    Figure imgb0560
         		500
    Figure imgb0561
         		501
    Figure imgb0562
    502
    Figure imgb0563
         		503
    Figure imgb0564
         		504
    Figure imgb0565
    505
    Figure imgb0566
         		506
    Figure imgb0567
         		507
    Figure imgb0568
    508
    Figure imgb0569
         		509
    Figure imgb0570
         		510
    Figure imgb0571
    511
    Figure imgb0572
         		512
    Figure imgb0573
         		513
    Figure imgb0574
    514
    Figure imgb0575
         		515
    Figure imgb0576
         		516
    Figure imgb0577
    517
    Figure imgb0578
         		518
    Figure imgb0579
         		519
    Figure imgb0580
    520
    Figure imgb0581
         		521
    Figure imgb0582
         		522
    Figure imgb0583
    523
    Figure imgb0584
         		524
    Figure imgb0585
         		525
    Figure imgb0586
    526
    Figure imgb0587
         		527
    Figure imgb0588
         		528
    Figure imgb0589
    529
    Figure imgb0590
         		530
    Figure imgb0591
         		531
    Figure imgb0592
    532
    Figure imgb0593
         		533
    Figure imgb0594
         		534
    Figure imgb0595
    535
    Figure imgb0596
         		536
    Figure imgb0597
         		537
    Figure imgb0598
    538
    Figure imgb0599
         		539
    Figure imgb0600
         		540
    Figure imgb0601
    541
    Figure imgb0602
         		542
    Figure imgb0603
         		543
    Figure imgb0604
    544
    Figure imgb0605
         		545
    Figure imgb0606
         		546
    Figure imgb0607
    547
    Figure imgb0608
         		548
    Figure imgb0609
         		549
    Figure imgb0610
    550
    Figure imgb0611
         		551
    Figure imgb0612
         		552
    Figure imgb0613
    553
    Figure imgb0614
         		554
    Figure imgb0615
         		555
    Figure imgb0616
    556
    Figure imgb0617
         		557
    Figure imgb0618
         		558
    Figure imgb0619
    559
    Figure imgb0620
         		560
    Figure imgb0621
         		561
    Figure imgb0622
    562
    Figure imgb0623
         		563
    Figure imgb0624
         		564
    Figure imgb0625
    565
    Figure imgb0626
         		566
    Figure imgb0627
         		567
    Figure imgb0628
    568
    Figure imgb0629
         		569
    Figure imgb0630
         		570
    Figure imgb0631
    571
    Figure imgb0632
         		572
    Figure imgb0633
         		573
    Figure imgb0634
    574
    Figure imgb0635
         		575
    Figure imgb0636
         		576
    Figure imgb0637
    577
    Figure imgb0638
         		578
    Figure imgb0639
         		579
    Figure imgb0640
    580
    Figure imgb0641
         		581
    Figure imgb0642
         		582
    Figure imgb0643
    583
    Figure imgb0644
         		584
    Figure imgb0645
         		585
    Figure imgb0646
    586
    Figure imgb0647
         		587
    Figure imgb0648
         		588
    Figure imgb0649
    589
    Figure imgb0650
         		590
    Figure imgb0651
         		591
    Figure imgb0652
    592
    Figure imgb0653
         		593
    Figure imgb0654
         		594
    Figure imgb0655
    595
    Figure imgb0656
         		596
    Figure imgb0657
         		597
    Figure imgb0658
    598
    Figure imgb0659
         		599
    Figure imgb0660
         		600
    Figure imgb0661
    601
    Figure imgb0662
         		602
    Figure imgb0663
         		603
    Figure imgb0664
    604
    Figure imgb0665
         		605
    Figure imgb0666
         		606
    Figure imgb0667
    607
    Figure imgb0668
         		608
    Figure imgb0669
         		609
    Figure imgb0670
    610
    Figure imgb0671
         		611
    Figure imgb0672
         		612
    Figure imgb0673
    613
    Figure imgb0674
         		614
    Figure imgb0675
         		615
    Figure imgb0676
    616
    Figure imgb0677
         		617
    Figure imgb0678
         		618
    Figure imgb0679
    619
    Figure imgb0680
         		620
    Figure imgb0681
         		621
    Figure imgb0682
    622
    Figure imgb0683
         		623
    Figure imgb0684
         		624
    Figure imgb0685
    625
    Figure imgb0686
         		626
    Figure imgb0687
         		627
    Figure imgb0688
    628
    Figure imgb0689
         		629
    Figure imgb0690
         		630
    Figure imgb0691
    631
    Figure imgb0692
         		632
    Figure imgb0693
         		633
    Figure imgb0694
    634
    Figure imgb0695
         		635
    Figure imgb0696
         		636
    Figure imgb0697
    637
    Figure imgb0698
         		638
    Figure imgb0699
         		639
    Figure imgb0700
    640
    Figure imgb0701
         		641
    Figure imgb0702
         		642
    Figure imgb0703
    643
    Figure imgb0704
         		644
    Figure imgb0705
         		645
    Figure imgb0706
    646
    Figure imgb0707
         		647
    Figure imgb0708
         		648
    Figure imgb0709
    649
    Figure imgb0710
         		650
    Figure imgb0711
         		651
    Figure imgb0712
    652
    Figure imgb0713
         		653
    Figure imgb0714
         		654
    Figure imgb0715
    655
    Figure imgb0716
         		656
    Figure imgb0717
         		657
    Figure imgb0718
    658
    Figure imgb0719
         		659
    Figure imgb0720
         		660
    Figure imgb0721
    661
    Figure imgb0722
         		662
    Figure imgb0723
         		663
    Figure imgb0724
    664
    Figure imgb0725
         		665
    Figure imgb0726
         		666
    Figure imgb0727
    667
    Figure imgb0728
         		668
    Figure imgb0729
         		669
    Figure imgb0730
    670
    Figure imgb0731
         		671
    Figure imgb0732
         		672
    Figure imgb0733
    673
    Figure imgb0734
         		674
    Figure imgb0735
         		675
    Figure imgb0736
    676
    Figure imgb0737
         		677
    Figure imgb0738
         		678
    Figure imgb0739
    679
    Figure imgb0740
         		680
    Figure imgb0741
         		681
    Figure imgb0742
    682
    Figure imgb0743
         		683
    Figure imgb0744
         		684
    Figure imgb0745
    685
    Figure imgb0746
         		686
    Figure imgb0747
         		687
    Figure imgb0748
    688
    Figure imgb0749
         		689
    Figure imgb0750
         		690
    Figure imgb0751
    691
    Figure imgb0752
         		692
    Figure imgb0753
         		693
    Figure imgb0754
    694
    Figure imgb0755
         		695
    Figure imgb0756
         		696
    Figure imgb0757
    697
    Figure imgb0758
         		698
    Figure imgb0759
         		699
    Figure imgb0760
    700
    Figure imgb0761
         		701
    Figure imgb0762
         		702
    Figure imgb0763
    703
    Figure imgb0764
         		704
    Figure imgb0765
         		705
    Figure imgb0766
    706
    Figure imgb0767
         		707
    Figure imgb0768
         		708
    Figure imgb0769
    709
    Figure imgb0770
         		710
    Figure imgb0771
         		711
    Figure imgb0772
    712
    Figure imgb0773
         		713
    Figure imgb0774
         		714
    Figure imgb0775
    715
    Figure imgb0776
         		716
    Figure imgb0777
         		717
    Figure imgb0778
    718
    Figure imgb0779
         		719
    Figure imgb0780
         		720
    Figure imgb0781
    721
    Figure imgb0782
         		722
    Figure imgb0783
         		723
    Figure imgb0784
    724
    Figure imgb0785
         		725
    Figure imgb0786
         		726
    Figure imgb0787
    727
    Figure imgb0788
         		728
    Figure imgb0789
         		729
    Figure imgb0790
    730
    Figure imgb0791
         		731
    Figure imgb0792
         		732
    Figure imgb0793
    733
    Figure imgb0794
         		734
    Figure imgb0795
         		735
    Figure imgb0796
    736
    Figure imgb0797
         		737
    Figure imgb0798
         		738
    Figure imgb0799
    739
    Figure imgb0800
         		740
    Figure imgb0801
         		741
    Figure imgb0802
    742
    Figure imgb0803
         		743
    Figure imgb0804
         		744
    Figure imgb0805
    745
    Figure imgb0806
         		746
    Figure imgb0807
         		747
    Figure imgb0808
    748
    Figure imgb0809
         		749
    Figure imgb0810
         		750
    Figure imgb0811
    751
    Figure imgb0812
         		752
    Figure imgb0813
         		753
    Figure imgb0814
    754
    Figure imgb0815
         		755
    Figure imgb0816
         		756
    Figure imgb0817
    757
    Figure imgb0818
         		758
    Figure imgb0819
         		759
    Figure imgb0820
    760
    Figure imgb0821
         		761
    Figure imgb0822
         		762
    Figure imgb0823
    763
    Figure imgb0824
         		764
    Figure imgb0825
         		765
    Figure imgb0826
    766
    Figure imgb0827
         		767
    Figure imgb0828
         		768
    Figure imgb0829
    769
    Figure imgb0830
         		770
    Figure imgb0831
         		771
    Figure imgb0832
    772
    Figure imgb0833
         		773
    Figure imgb0834
         		774
    Figure imgb0835
    775
    Figure imgb0836
         		776
    Figure imgb0837
         		777
    Figure imgb0838
    778
    Figure imgb0839
         		779
    Figure imgb0840
         		780
    Figure imgb0841
    781
    Figure imgb0842
         		782
    Figure imgb0843
         		783
    Figure imgb0844
    784
    Figure imgb0845
         		785
    Figure imgb0846
         		786
    Figure imgb0847
    787
    Figure imgb0848
         		788
    Figure imgb0849
         		789
    Figure imgb0850
    790
    Figure imgb0851
         		791
    Figure imgb0852
         		792
    Figure imgb0853
    793
    Figure imgb0854
         		794
    Figure imgb0855
         		795
    Figure imgb0856
    796
    Figure imgb0857
         		797
    Figure imgb0858
         		798
    Figure imgb0859
    799
    Figure imgb0860
         		800
    Figure imgb0861
         		801
    Figure imgb0862
    802
    Figure imgb0863
         		803
    Figure imgb0864
         		804
    Figure imgb0865
    805
    Figure imgb0866
         		806
    Figure imgb0867
         		807
    Figure imgb0868
    808
    Figure imgb0869
         		809
    Figure imgb0870
         		810
    Figure imgb0871
    811
    Figure imgb0872
         		812
    Figure imgb0873
         		813
    Figure imgb0874
    814
    Figure imgb0875
         		815
    Figure imgb0876
         		816
    Figure imgb0877
    817
    Figure imgb0878
         		818
    Figure imgb0879
         		819
    Figure imgb0880
    820
    Figure imgb0881
         		821
    Figure imgb0882
         		822
    Figure imgb0883
    823
    Figure imgb0884
         		824
    Figure imgb0885
         		825
    Figure imgb0886
    826
    Figure imgb0887
         		827
    Figure imgb0888
         		828
    Figure imgb0889
    829
    Figure imgb0890
         		830
    Figure imgb0891
         		831
    Figure imgb0892
    832
    Figure imgb0893
         		833
    Figure imgb0894
         		834
    Figure imgb0895
    835
    Figure imgb0896
         		836
    Figure imgb0897
         		837
    Figure imgb0898
    838
    Figure imgb0899
         		839
    Figure imgb0900
         		840
    Figure imgb0901
    841
    Figure imgb0902
         		842
    Figure imgb0903
         		843
    Figure imgb0904
    844
    Figure imgb0905
         		845
    Figure imgb0906
         		846
    Figure imgb0907
    847
    Figure imgb0908
         		848
    Figure imgb0909
         		849
    Figure imgb0910
    850
    Figure imgb0911
         		851
    Figure imgb0912
         		852
    Figure imgb0913
    853
    Figure imgb0914
         		854
    Figure imgb0915
         		855
    Figure imgb0916
    856
    Figure imgb0917
         		857
    Figure imgb0918
         		858
    Figure imgb0919
    859
    Figure imgb0920
         		860
    Figure imgb0921
         		861
    Figure imgb0922
    862
    Figure imgb0923
         		863
    Figure imgb0924
         		864
    Figure imgb0925
    865
    Figure imgb0926
         		866
    Figure imgb0927
         		867
    Figure imgb0928
    868
    Figure imgb0929
         		869
    Figure imgb0930
         		870
    Figure imgb0931
    871
    Figure imgb0932
         		872
    Figure imgb0933
         		873
    Figure imgb0934
    874
    Figure imgb0935
         		875
    Figure imgb0936
         		876
    Figure imgb0937
    877
    Figure imgb0938
         		878
    Figure imgb0939
         		879
    Figure imgb0940
    880
    Figure imgb0941
         		881
    Figure imgb0942
         		882
    Figure imgb0943
    883
    Figure imgb0944
         		884
    Figure imgb0945
         		885
    Figure imgb0946
    886
    Figure imgb0947
         		887
    Figure imgb0948
         		888
    Figure imgb0949
    889
    Figure imgb0950
         		890
    Figure imgb0951
         		891
    Figure imgb0952
    892
    Figure imgb0953
         		893
    Figure imgb0954
         		894
    Figure imgb0955
    895
    Figure imgb0956
         		896
    Figure imgb0957
         		897
    Figure imgb0958
    898
    Figure imgb0959
         		899
    Figure imgb0960
         		900
    Figure imgb0961
    901
    Figure imgb0962
         		902
    Figure imgb0963
         		903
    Figure imgb0964
    904
    Figure imgb0965
         		905
    Figure imgb0966
         		906
    Figure imgb0967
    907
    Figure imgb0968
         		908
    Figure imgb0969
         		909
    Figure imgb0970
    910
    Figure imgb0971
         		911
    Figure imgb0972
         		912
    Figure imgb0973
    913
    Figure imgb0974
         		914
    Figure imgb0975
         		915
    Figure imgb0976
    916
    Figure imgb0977
         		917
    Figure imgb0978
         		918
    Figure imgb0979
    919
    Figure imgb0980
         		920
    Figure imgb0981
         		921
    Figure imgb0982
    922
    Figure imgb0983
         		923
    Figure imgb0984
         		924
    Figure imgb0985
    925
    Figure imgb0986
         		926
    Figure imgb0987
         		927
    Figure imgb0988
    928
    Figure imgb0989
         		929
    Figure imgb0990
         		930
    Figure imgb0991
    931
    Figure imgb0992
         		932
    Figure imgb0993
         		933
    Figure imgb0994
    934
    Figure imgb0995
         		935
    Figure imgb0996
         		936
    Figure imgb0997
    937
    Figure imgb0998
         		938
    Figure imgb0999
         		939
    Figure imgb1000
    940
    Figure imgb1001
         		941
    Figure imgb1002
         		942
    Figure imgb1003
    943
    Figure imgb1004
         		944
    Figure imgb1005
         		945
    Figure imgb1006
    946
    Figure imgb1007
         		947
    Figure imgb1008
         		948
    Figure imgb1009
    949
    Figure imgb1010
         		950
    Figure imgb1011
         		951
    Figure imgb1012
    952
    Figure imgb1013
         		953
    Figure imgb1014
         		954
    Figure imgb1015
    955
    Figure imgb1016
         		956
    Figure imgb1017
         		957
    Figure imgb1018
    958
    Figure imgb1019
         		959
    Figure imgb1020
         		960
    Figure imgb1021
    961
    Figure imgb1022
         		962
    Figure imgb1023
         		963
    Figure imgb1024
    964
    Figure imgb1025
         		965
    Figure imgb1026
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    • Administration and Pharmaceutical Compositions
  • Some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of the 1H-pyrazolo[3,4-b]pyridine compound, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.
  • The compounds of this invention may also be useful in combination (administered together or sequentially) with other known agents.
  • Non-limiting examples of diseases which can be treated with a combination of a compound of Formulas (I) or (II) and other known agents are colorectal cancer, ovarian cancer, retinitis pigmentosa, macular degeneration, idiopathic pulmonary fibrosis and osteoarthritis.
  • In some embodiments, colorectal cancer can be treated with a combination of a compound of either Formulas (I) or (II) and one or more of the following drugs: 5-Fluorouracil (5-FU), which is often given with the vitamin-like drug leucovorin (also called folinic acid); Capecitabine (Xeloda®), Irinotecan (Camptosar®), Oxaliplatin (Eloxatin®). Examples of combinations of these drugs which could be further combined with a compound of either Formulas (I) or (II) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectal cancer, chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).
  • In some embodiments, ovarian cancer can be treated with a combination of a compound of either Formulas (I) or (II) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (Doxil®), Gemcitabine (Gemzar®), Cyclophosphamide (Cytoxan®), Vinorelbine (Navelbine®), Ifosfamide (Ifex®), Etoposide (VP-16), Altretamine (Hexalen®), Capecitabine (Xeloda®), Irinotecan (CPT-11, Camptosar®), Melphalan, Pemetrexed (Alimta®) and Albumin bound paclitaxel (nab-paclitaxel, Abraxane®). Examples of combinations of these drugs which could be further combined with a compound of either Formulas (I) or (II) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP (etoposide [VP-16], ifosfamide, and cisplatin).
  • In some embodiments, a compound of either Formulas (I) or (II) can be used to treat cancer in combination with any of the following methods: (a) Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) Ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy and cryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy using anti-metabolites such as azathioprine and mercaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) and taxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposide and docetaxel; (g) Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i) Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate (Gleevec®, also known as STI-571), Gefitinib (Iressa, also known as ZD1839), Erlotinib (marketed as Tarceva®), Bortezomib (Velcade®), tamoxifen , tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax in clinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib in clinical trials), PI3K inhibitors (eg. perifosine in a phase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MabThera® or Rituxan®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as Erbitux®) and Bevacizumab (marketed as Avastin®); and (k) radiation therapy.
  • In some embodiments, idiopathic pulmonary fibrosis can be treated with a combination of a compound of either Formulas (I) or (II) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprine, N-acetylcysteine, interferon-γ 1b, bosentan (bosentan is currently being studied in patients with IPF, [The American Journal of Respiratory and Critical Care Medicine (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 and Vargatef), QAX576 [ British Journal of Pharmacology (2011), 163(1), 141-172], and anti-inflammatory agents such as corticosteroids.
  • In some embodiments, a compound of either Formulas (I) or (II) can be used to treat idiopathic pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery.
  • In some embodiments, a compound of either Formulas (I) or (II) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine; (f) in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices); (g) realigning bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with a chronic pain class.
  • In some embodiments, macular degeneration can be treated with a combination of a compound of either Formulas (I) or (II) and one or more of the following drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®), Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfin (Visudyne®) in combination with photodynamic therapy (PDT) or with any of the following methods: (a) in combination with laser to destroy abnormal blood vessels (photocoagulation); and (b) in combination with increased vitamin intake of antioxidant vitamins and zinc.
  • In some embodiments, retinitis pigmentosa can be treated with a combination of a compound of either Formulas (I) or (II) and one or more of the following drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurin or with any of the following methods: (a) with the Argus® II retinal implant; and (b) with stem cell and/or gene therapy.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutical compositions as provided herein may be formulated as solids, semi solids, liquids, solutions, colloidals, liposomes, emulsions, suspensions, complexes, coacervates, or aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like are also provided herein. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. Preferably, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. Preferably, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • The compounds can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from nontoxic carrier may be prepared. The contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).
  • In one preferred embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which the two active ingredients are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension. If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 0.25 mg/Kg to 50 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 0.25 mg/Kg to 20 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 0.50 mg/Kg to 19 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 0.75 mg/Kg to 18 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 1.0 mg/Kg to 17 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 1.25 mg/Kg to 16 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 1.50 mg/Kg to 15 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 1.75 mg/Kg to 14 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 2.0 mg/Kg to 13 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 3.0 mg/Kg to 12 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) is 4.0 mg/Kg to 11 mg/Kg in humans.
  • In some embodiments, the unit dosage of compounds of Formulas (I) or (II) is 5.0 mg/Kg to 10 mg/Kg in humans.
  • In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration of a precise dose.
  • In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration of a precise dose.
  • Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.
  • In some embodiments, the composition will comprise 0.1-10% of the active agent in solution.
  • In some embodiments, the composition will comprise 0.1-5% of the active agent in solution.
  • In some embodiments, the composition will comprise 0.1-4% of the active agent in solution.
  • In some embodiments, the composition will comprise 0.15-3% of the active agent in solution.
  • In some embodiments, the composition will comprise 0.2-2% of the active agent in solution.
  • In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-96 hours.
  • In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-72 hours.
  • In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-48 hours.
  • In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-24 hours.
  • In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-12 hours.
  • In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-6 hours.
  • In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m2 to 300 mg/m2.
  • In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m2 to 200 mg/m2.
  • In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m2 to 100 mg/m2.
  • In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 10 mg/m2 to 50 mg/m2.
  • In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 50 mg/m2 to 200 mg/m2.
  • In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 75 mg/m2 to 175 mg/m2.
  • In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 100 mg/m2 to 150 mg/m2.
  • It is to be noted that concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
  • In one preferred embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique.
  • In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size is desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth. For optimal delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 µm are useful, with an aerodynamic particle size of about 1 to about 10 microns being preferred. Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.
  • In some embodiments, compounds of Formulas (I) or (II) disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose® or the AERx® systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.
  • In some embodiments, the compositions of Formulas (I) or (II) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873 ) can be used.
  • Alternatively, formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484 ) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559 ).
  • If desired, formulations of the invention can be incorporated into a gel formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211 ).
  • In some embodiments, compounds of Formulas (I) or (II) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.
  • Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments, compounds of Formulas (I) or (II) can be delivered from the reservoir of an external or internal implanted pumping system.
  • Formulations of the invention also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815 ).
  • Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, the formulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional embodiments, the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
  • In some embodiments, the compounds of Formulas (I) or (II) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.
  • Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the drug is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.
  • Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In a preferred embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound.
  • On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound.
  • Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
  • Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided above, and directions for use of the kit (e.g., instructions for treating a patient). In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer. In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome
  • The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
    • Methods of Treatment
  • The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more members of the Wnt pathway, which may include one or more Wnt proteins, and thus can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, rheumatoid arthritis, scleroderma, sarcoidosis, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neuron disease, Down's syndrome, frontotemporal dementia (FTDP-17), Pick's disease, surpanuclear palsy, corticobasal degeneration, multiple sclerosis or autism, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, retinal tumors, early coronary disease, tetra-amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
  • With respect to cancer, the Wnt pathway is known to be constitutively activated in a variety of cancers including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer , pancreatic cancer and leukemias such as CML, CLL, T-ALL, myelodysplastic syndromes and Mantle Cell Lympohomas. The constitutive activation is due to constitutively active β-catenin, perhaps due to its stabilization by interacting factors or inhibition of the degradation pathway. Accordingly, the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated. In certain embodiments, the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.
  • Other cancers can also be treated with the compounds and compositions described herein.
  • More particularly, cancers that may be treated by the compound, compositions and methods described herein include, but are not limited to, the following:
    1. 1) Breast cancers, including, for example ER+breast cancer, ER- breast cancer, her2- breast cancer, her2+ breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and miscellaneous malignant neoplasms. Further examples of breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER-), progesterone receptor negative, and her2 negative (her2-). In some embodiments, the breast cancer may have a high risk Oncotype score.
    2. 2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.
    3. 3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.
    4. 4) Gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.
    5. 5) Genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma.
    6. 6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.
    7. 7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.
    8. 8) Nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma.
    9. 9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma.
    10. 10) Hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenström's macroglobulinemia.
    11. 11) Skin cancers and skin disorders, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, desmoid tumors, and scleroderma.
    12. 12) Adrenal gland cancers, including, for example, neuroblastoma.
  • Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term "tumor cell," as provided herein, includes a cell afflicted by any one of the above identified disorders.
  • A method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be administered before, during, or after another anticancer agent or treatment.
  • The compounds and compositions described herein can be used as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular proliferation mediated by protein kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition.
  • In addition, and including treatment of cancer, the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient. Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders. Furthermore, such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells
  • Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following:
    • a variety of cancers, including, but not limited to, carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi's sarcoma.
    • a disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; idiopathic pulmonary fibrosis (IPF); fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neurodegenerative disorders such as Alzheimer's Disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis.
    • defective apoptosis-associated conditions, such as cancers (including but not limited to those types mentioned herein), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, rheumatoid arthritis, scleroderma, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.
    • genetic diseases due to mutations in Wnt signaling components, such as polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome and Rett syndrome.
  • Furthermore, the compounds and compositions described herein can be used to treat neurological conditions, disorders and/or diseases caused by dysfunction in the Wnt signaling pathway. Non-limiting examples of neurological conditions/disorders/diseases which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrile seizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barré syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly, macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, etachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neurone disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease and Zellweger syndrome.
  • The compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.
  • In some embodiment, the invention provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formulas (I) or (II), in combination (simultaneously or sequentially) with at least one other agent.
  • In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • In some embodiments, the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the disorder or disease is cancer.
  • In some embodiments, the disorder or disease is diabetic retinopathy.
  • In some embodiments, the disorder or disease is pulmonary fibrosis.
  • In some embodiments, the disorder or disease is idiopathic pulmonary fibrosis (IPF).
  • In some embodiments, the disorder or disease is rheumatoid arthritis.
  • In some embodiments, the disorder or disease is scleroderma.
  • In some embodiments, the disorder or disease is a mycotic or viral infection.
  • In some embodiments, the disorder or disease is a bone or cartilage disease.
  • In some embodiments, the disorder or disease is Alzheimer's disease.
  • In some embodiments, the disorder or disease is dementia.
  • In some embodiments, the disorder or disease is Parkinson's disease.
  • In some embodiments, the disorder or disease is osteoarthritis.
  • In some embodiments, the disorder or disease is lung disease
  • In some embodiments, the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Mullerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
  • In some embodiments, the patient is a human.
  • In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.
  • In some embodiments, the cancer is chosen from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer - melanoma, small intestine cancer, stomach cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal cortical cancer.
  • In some embodiments, the cancer is hepatocellular carcinoma.
  • In some embodiments, the cancer is colon cancer.
  • In some embodiments, the cancer is breast cancer.
  • In some embodiments, the cancer is pancreatic cancer.
  • In some embodiments, the cancer is chronic myeloid leukemia (CML).
  • In some embodiments, the cancer is chronic myelomonocytic leukemia.
  • In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).
  • In some embodiments, the cancer is acute myeloid leukemia.
  • In some embodiments, the cancer is acute lymphocytic leukemia.
  • In some embodiments, the cancer is Hodgkin lymphoma.
  • In some embodiments, the cancer is lymphoma.
  • In some embodiments, the cancer is sarcoma.
  • In some embodiments, the cancer is ovarian cancer.
  • In some embodiments, the cancer is lung cancer - non-small cell.
  • In some embodiments, the cancer is lung cancer - small cell.
  • In some embodiments, the cancer is multiple myeloma.
  • In some embodiments, the cancer is nasopharyngeal cancer.
  • In some embodiments, the cancer is neuroblastoma.
  • In some embodiments, the cancer is osteosarcoma.
  • In some embodiments, the cancer is penile cancer.
  • In some embodiments, the cancer is pituitary tumors.
  • In some embodiments, the cancer is prostate cancer.
  • In some embodiments, the cancer is retinoblastoma.
  • In some embodiments, the cancer is rhabdomyosarcoma.
  • In some embodiments, the cancer is salivary gland cancer.
  • In some embodiments, the cancer is skin cancer - basal and squamous cell.
  • In some embodiments, the cancer is skin cancer - melanoma.
  • In some embodiments, the cancer is small intestine cancer.
  • In some embodiments, the cancer is stomach cancers.
  • In some embodiments, the cancer is testicular cancer.
  • In some embodiments, the cancer is thymus cancer.
  • In some embodiments, the cancer is thyroid cancer.
  • In some embodiments, the cancer is uterine sarcoma.
  • In some embodiments, the cancer is vaginal cancer.
  • In some embodiments, the cancer is vulvar cancer.
  • In some embodiments, the cancer is Wilms tumor.
  • In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.
  • In some embodiments, the cancer is kidney cancer.
  • In some embodiments, the cancer is Kaposi sarcoma.
  • In some embodiments, the cancer is gestational trophoblastic disease.
  • In some embodiments, the cancer is gastrointestinal stromal tumor.
  • In some embodiments, the cancer is gastrointestinal carcinoid tumor.
  • In some embodiments, the cancer is gallbladder cancer.
  • In some embodiments, the cancer is eye cancer (melanoma and lymphoma).
  • In some embodiments, the cancer is Ewing tumor.
  • In some embodiments, the cancer is esophagus cancer.
  • In some embodiments, the cancer is endometrial cancer.
  • In some embodiments, the cancer is colorectal cancer.
  • In some embodiments, the cancer is cervical cancer.
  • In some embodiments, the cancer is brain or spinal cord tumor.
  • In some embodiments, the cancer is bone metastasis.
  • In some embodiments, the cancer is bone cancer.
  • In some embodiments, the cancer is bladder cancer.
  • In some embodiments, the cancer is bile duct cancer.
  • In some embodiments, the cancer is anal cancer.
  • In some embodiments, the cancer is adrenal cortical cancer.
  • In some embodiments, the disorder or disease is a neurological condition, disorder or disease, wherein the neurological condition/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and Charcot-Marie-Tooth disease.
  • In some embodiments, the compound of Formulas (I) or (II) inhibits one or more proteins in the Wnt pathway.
  • In some embodiments, the compound of Formulas (I) or (II) inhibits signaling induced by one or more Wnt proteins.
  • In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.
  • In some embodiments, the compound of Formulas (I) or (II) inhibits a kinase activity.
  • In some embodiments, the method of treats a disease or disorder mediated by the Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the compound of Formulas (I) or (II) inhibits one or more Wnt proteins.
  • In some embodiments, the method of treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.
  • In some embodiments, the method of inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound (or compounds) of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the method of treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprising administering to the patient a pharmaceutical composition comprising one or more of the compounds of Formulas (I) or (II) in combination with a pharmaceutically acceptable carrier and one or more other agents
  • Moreover, the compounds and compositions, for example, as inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.
  • Compounds and compositions described herein can inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the G.0, G.1 or mitotic stage of the cell cycle, e.g., CDK1, CDK2, CDK4, and/or CDK6 complexes.
    • Evaluation of Biological Activity
  • The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, e.g., WO 2001/053268 or WO 2005/009997 . For example, the activity of a compound may be tested using one or more of the test methods outlined below.
  • In one example, tumor cells may be screened for Wnt independent growth. In such a method, tumor cells of interest are contacted with a compound (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored. In some embodiments, tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above.
  • In another example, one may utilize in vitro assays for Wnt biological activity, e.g. stabilization of β-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of β-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition. An exemplary assay for Wnt biological activity contacts a Wnt composition in the presence of a candidate inhibitor with cells, e.g. mouse L cells. The cells are cultured for a period of time sufficient to stabilize β-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for β-catenin.
  • In a further example, the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell (1997), 88(6), 747-756).
  • To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.
    • EXAMPLES Compound preparation
  • The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.
  • It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7th Ed., John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5th Ed., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2nd Ed., John Wiley & Sons (1999) (incorporated herein by reference in its entirety)and the like.
  • The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety.
  • Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention.
  • (1H) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for 1H or Avance TM DRX500, 500 MHz for 1H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for 1H). Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; m, multiplet.
  • The following abbreviations have the indicated meanings:
    • n-BuOH = n-butyl alcohol
    • brine = saturated aqueous sodium chloride
    • CDCl3 = deuterated chloroform
    • CDI = 1,1'-carbonyldiimidazole
    • DCE = dichloroethane
    • DCM= dichloromethane
    • DIPEA = diisopropylethylamine
    • DMF= N,N-dimethylformamide
    • DMSO-d6 = deuterated dimethylsulfoxide
    • EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
    • ESIMS = electron spray mass spectrometry
    • EtOAc = ethyl acetate
    • EtOH = ethanol
    • HCl = hydrochloric acid
    • HOAc = acetic acid
    • H2SO4 = sulfuric acid
    • K3CO4 = potassium carbonate
    • KMnO4 = potassium permanganate
    • KOAc = potassium acetate
    • KOtBu = potassium t-butoxide
    • K3PO4 = potassium phosphate
    • LDA = lithium diisopropylamide
    • MeOH = methanol
    • MgSO4 = magnesium sulfate
    • NaBH(OAc)3 = sodium triacetoxyborohydride
    • NaCNBH3 = sodium cyanoborohydride
    • NaHCO3 = sodium bicarbonate
    • NaHSO4 = sodium bisulfate
    • NaOAc = sodium acetate
    • NaOCl = sodium hypochlorite
    • NaOH = sodium hydroxide
    • Na2S2O3*7H2O = sodium thiosulfate pentahydrate
    • NH4OH = ammonium hydroxide
    • NMR = nuclear magnetic resonance
    • Pd/C = palladium(0) on carbon
    • Pd(dppf)2Cl2 = 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride
    • Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0)
    • Pd(PPh3)2Cl2 = bis(triphenylphosphine)palladium(II) chloride
    • PPTS = pyridinium p-toluenesulfonate
    • r.t. = room temperature
    • S(0) = elemental sulfur
    • TEA = triethylamine
    • TEMPO = (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethyl piperidin-1-yl)oxidanyl
    • TFA = trifluoroacetic acid
    • THF = tetrahydrofuran
    • TLC = thin layer chromatography
    • TrCl = triphenylmethyl chloride or trityl chloride
  • The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application. Unless otherwise indicated, all variables are as defined above.
    • General procedures
  • Compounds of Formulas (I) or (II) of the present invention can be prepared as depicted in Scheme 1.
    Figure imgb1050
  • Scheme 1 describes a method for preparation of 1H-pyrazolo[3,4-b]pyridine derivatives (VIII) by reacting aldehyde III with various boronic acid derivatives (XII) under Suzuki coupling conditions to give aldehyde V. Aldehyde V is reacted with various substituted and unsubstituted aryl/heteroaryl-3,4-diamines (VI) to form VII. Final deprotection of the pyrazolone nitrogen yields the desired 1H-pyrazolo[3,4-b]pyridine derivative (VIII).
  • Compounds of Formulas (I) or (II) of the present invention can also be prepared as depicted in Scheme 2.
    Figure imgb1051
  • Scheme 2 describes an alternative method for preparation of 1H-pyrazolo[3,4-b]pyridine derivatives (VIII) by reacting 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (III) with bis(pinacolato)diboron to form the borate ester (IX). Suzuki coupling with various bromides (X) or chlorides yields 1H-pyrazolo[3,4-b]pyridine derivatives (V). Aldehyde (V) is reacted with various 1,2-diamines (VI) to produce (VII). Final deprotection of the pyrazole nitrogen yields the desired 1H-pyrazolo[3,4-b]pyridine derivatives (VIII).
    • Illustrative Compound Examples
  • Synthesis of intermediate 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (III) is depicted below in Scheme 3.
    Figure imgb1052
    Figure imgb1053
    • Step 1
  • A solution of 2-chloropyridine (XI) (9.39 mL, 0.1 mol) in anhydrous THF (50 mL) was added slowly to a solution of LDA (2.0 M solution in THF/hexane/ethylbenzene, 50 mL, 0.1 mol) in THF (200 mL) stirred at -78°C under nitrogen. The stirring was continued at -78°C for an additional 3 h before adding acetaldehyde (6.17 mL, 0.110 mol). The solution was stirred at -78°C for another 2 h before allowing the temperature to rise to -40°C. A solution of water (4 mL) in THF (40 mL) was added slowly to the solution. When the temperature reached -10°C, additional water (200 mL) was added to the solution. The solution was extracted with ethyl ether (3 x 100 mL). The combined organic phase was dried over MgSO4, filtered and evaporated under reduced pressure to get a brown viscous residue. The crude product was purified on a flash silica gel column (1:1 DCM:hexane→100% DCM) to produce 1-(2-chloropyridin-3-yl)ethanol (XII) as a brown viscous oil (6 g, 38.1 mmol, 38% yield). 1H NMR (CDCl3) δ ppm 1.52 (d, J=6.41Hz, 3H), 2.51 (brs, 1H), 5.24 (m, 1H), 7.28 (m, 1 H), 7.97 (dd, J=7.72Hz, J=1.70Hz, 1H), 8.27 (dd, J=7.72Hz, J=1.79Hz, 1H).
    • Step 2
  • To a solution of 1-(2-chloropyridin-3-yl)ethanol (XII) in dry acetone at -30°C under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30°C and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCO3 solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1-(2-chloropyridin-3-yl)ethanone (XIII) as a brown liquid (0.72 g, 4.63 mmol, 77% yield). 1H NMR (CDCl3) δ ppm 2.71 (s, 3H), 7.35 (dd, J=7.63Hz, J=4.80Hz, 1H), 7.91 (dd, J=7.54Hz, J=1.88Hz, 1H), 8.55 (dd, J=4.71Hz, J=1.88Hz, 1H).
    • Step 3
  • To a solution of 1-(2-Chloropyridin-3-yl)ethanone (XIII) (0.311 g, 2 mmol) in n-butanol (10 mL) was added hydrazine hydrate (1.45 mL, 30 mmol). The reaction was refluxed overnight. The solution was cooled and the solvent was evaporated under vacuum. The residue was dissolved in DCM and washed successively by water and brine. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) as a white solid (192 mg, 1.44 mmol, 72% yield). 1H NMR (CDCl3) δ ppm 2.64 (s, 3 H), 7.14 (dd, J=8.01Hz, J=4.62Hz, 1H), 8.14 (dd, J=7.54Hz, J=1.88Hz, 1H), 8.59 (dd, J=4.52Hz, J=1.32Hz, 1H), 11.68 (brs, 1H).
    • Step 4
  • To a solution of NaOH (0.88 g, 22 mmol) in water (20 mL) was added 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) (0.4 g, 3 mmol). The suspension was heated at 80°C until a clear solution was obtained. A solution of KMnO4 (1.73 g, 11 mmol) in water (180 mL) was added slowly over 2 h while heating the solution at 80°C. The solution was heated at 90°C for an additional 2 h until the complete disappearance of starting material was observed by TLC. The solution was cooled to 70°C and filtered through a pad of Celite. The solids were washed by boiling water. The combined filtrate was cooled to 0°C, acidified with conc. H2SO4 to pH=2 and extracted with n-butanol (2 x 10 mL). The n-butanol layer was concentrated under reduced pressure to get a white residue which was dissolved in DCM by adding minimum amount of MeOH and then filtered. The filtrate was concentrated to give 1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XV) as a white solid (390 mg, 2.39 mmol, 81% yield). 1H NMR (CDCl3) δ ppm 7.37 (dd, J=8.10Hz, J=4.52Hz, 1H), 8.47 (dd, J=7.54Hz, J=1.88Hz, 1H), 8.62 (dd, J=4.52Hz, J=1.32Hz, 1H), 14.37 (brs, 1H).
    • Step 5
  • To a solution of 1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (XV) (0.39 g, 2.4 mmol) in dry MeOH (10 mL) was added concentrated H2SO4 (4 drops) and refluxed for 6 h under nitrogen. The solution was cooled and the solvent was evaporated under vacuum. The residue was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified on a flash silica gel column (100% DCM →3:97 MeOH:DCM) to produce methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVI) as a white solid (382 mg, 2.16 mmol, 90% yield). 1H NMR (CDCl3) δ ppm 4.08 (s, 3H), 7.38 (m, 1H), 8.63 (dd, J=8.10Hz, J=1.51Hz, 1H), 8.72 (dd, J=4.62Hz, J=1.41Hz, 1H); ESIMS found for C8H7N3O2 m/z 178.2 (M+H).
    • Step 6
  • A mixture of methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVI) (0.177 g, 1 mmol), sodium acetate (0.492 g, 6 mmol) and bromine (0.308 mL, 6 mmol) in glacial acetic acid (5 mL) was heated overnight at 120°C in a sealed tube. The solution was cooled and poured into water. The solids formed were filtered, washed with water and dried at room temperature under vacuum. The crude product was purified on a flash silica gel column (100% DCM →2:98 MeOH:DCM) to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) as a white solid (78 mg, 0.31 mmol, 30% yield). 1H NMR (CDCl3) δ ppm 3.95 (s, 3H), 8.62 (d, J=3.01Hz, 1H), 8.73 (d, J=3.01Hz, 1H); ESIMS found for C8H6BrN3O2 m/z 256.3 (M+H).
    • Step 7
  • A suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (70 mg, 0.27 mmol) in aqueous IN NaOH solution (20 mL) was heated at 90°C for 3 h until the solution became clear. The solution was then cooled to 0°C and acidified with a 10% HCl solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) as a white solid (60 mg, 0.25 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 8.58 (d, J=3.01Hz, 1H), 8.66 (d, J=3.01Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
    • Step 8
  • To a solution of 5-bromo-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (XVIII) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65°C under nitrogen. The solution was cooled to room temperature and N,O-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65°C under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10% HCl solution, a saturated aqueous NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XIX) as a white solid (260 mg, 0.91 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01Hz, 1H), 8.67 (d, J=3.01Hz, 1H); ESIMS found for C9H9BrN4O2 m/z 285.4 (M+H).
    • Step 9
  • To a solution of 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XIX) (0.250 g, 0.88 mmol) in dry DCM (10 mL) was added 3,4-dihydro-2H-pyran (0.179 mL, 1.98 mmol) and PPTS (22 mg, 0.08 mmol) and refluxed 5 h under nitrogen. Another equivalent of 3,4-dihydro-2H-pyran (0.179 mL, 1.98 mmol) and PPTS (22 mg, 0.08 mmol) was added and the solution was further heated at refluxed overnight under nitrogen. The solution was cooled, diluted with DCM, washed subsequently with a saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 5-bromo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XX) as a viscous liquid (302 mg, 0.82 mmol, 93% yield). 1H NMR (CDCl3) δ ppm 1.51-1.62 (m, 2H), 1.91-2.13 (m, 2H), 2.33-2.44 (m, 2H), 3.40 (s, 3H), 3.66 (m, 1H), 3.75 (s, 3H), 3.87-3.98 (m, 1H), 6.07 (dd, J=10.07Hz, J=2.52Hz, 1H), 8.57 (d, J=3.01Hz, 1H), 8.73 (d, J=3.01Hz, 1H); ESIMS found for C14H17BrN4O3 m/z 369.4 (M+H).
    • Step 10
  • To a solution of 5-bromo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (XX) (0.290 g, 0.78) in dry THF (5 mL) stirred at 0°C under nitrogen was added lithium aluminum hydride (36 mg, 0.94 mmol). The solution was further stirred at 0°C for 30 min. The reaction was quenched with a 0.4 N NaHSO4 solution (10 mL). The solution was extracted with DCM (3 x 15 mL). The combined organic layer was washed subsequently with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (III) as a viscous liquid (218 mg, 0.70 mmol, 91% yield). 1H NMR (CDCl3) δ ppm 1.52-1.74 (m, 2H), 1.95-2.18 (m, 2H), 2.37-2.49 (m, 2H) 3.87-3.98 (m, 1H), 3.99 (m, 1H), 6.18 (dd, J=10.20Hz, J=2.39Hz, 1H), 8.73 (d, J=3.01Hz, 1H), 8.85 (d, J=3.01Hz, 1H), 10.16 (s, 1H); ESIMS found for C12H12BrN3O2 m/z 310.4 (M+H).
  • Synthesis of intermediate 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XI) is depicted below in Scheme 4.
    Figure imgb1054
    Figure imgb1055
    • Step 1-2
  • To a solution of 2-chloropyridine (XI) (31.0 kg, 273 mol) in dry THF (275 L) cooled to -78°C under nitrogen was added LDA (113 L, 1220 mol) dropwise while maintaining the temperature at -78°C and stirred for 5 hours. Acetaldehyde (16 L, 463 mol) was then added and the reaction was stirred at -78°C for another 5 hours before warming to 0°C and adding water (310 L) to quench the reaction. The solution was stirred for 50 min and then warmed to room temperature. The solution was extracted 3 x EtOAc (279 L) by adding EtOAc, stirring for 50 min, allowing to stand for 50 min, separating the layers and then repeating twice. The combined EtOAc was concentrated under vacuum to a volume of 300-500 L. To the crude 1-(2-chloropyridin-3-yl)ethanol (XII) was added DCM (705 L) followed by an aqueous solution of KBr (3.3 Kg, 27.7 mol) dissolved in water (33 L). The solution was cooled to 0°C before adding TEMPO (1.7 Kg, 10.9 mol) and then stirred for 50 min. In a second container, water (980 L) was added followed by KHCO3 (268 Kg, 2677 mol) and 10% aqueous NaClO (233 L, 313 mol). This aqueous mixture was then added dropwise to the TEMPO mixture. This combined mixture was stirred at 0°C for 5 hours. To this mixture was added dropwise Na2S2O3*7H2O (22.5 Kg, 90 mol) in water (107 L) with stirring for 50 min at 0°C. The mixture was allowed to warm to room temperature and the organic phase was separated. The aqueous phase was extracted 2 x DCM (353 L) by adding DCM, stirring for 50 min, allowing to stand for 50 min, separating the layers and then repeating. The combined organic layers were washed with aqueous 25% NaCl (274 L) and concentrated under vacuum to give crude 1-(2-chloropyridin-3-yl)ethanone (XIII) which was used for the next step without additional purification.
    • Step 3
  • To a solution of the above crude 1-(2-chloropyridin-3-yl)ethanone (XIII) in n-BuOH (512 L) was added 85% hydrazine hydrate (78 L, 1360 mol). The reaction was heated at refluxed (∼120°C) for 48 hours. The reaction was cooled and evaporated under vacuum. The crude material was taken up in DCM (834 L) and washed with 2 x aqueous 25% NaCl (214 L) by adding aqueous 25% NaCl, stirring for 50 min, allowing to stand for 50 min, separating the layers and then repeating. The organic layer was evaporated to produce 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) as a solid (13.2 Kg, 99 mol, 94.1% purity, 36.3% assay yield for 3 steps). 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.50 (s, 3H), 7.13 (dd, J=4.4Hz, J=8Hz, 1H), 8.19 (dd, J=1.2Hz, J=8Hz, 1H), 8.47 (dd, J=1.6Hz, J=4.8Hz, 1H), 13.18 (brs, 1H); ESIMS found C7H7N3 m/z 133.8 (M+H).
    • Step 4
  • To a solution of 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) (12.7 Kg, 95.4 mol) in HOAc (57 L) was added NaOAc (20.4 Kg, 248 mol), water (13.3 L), and Br2 (40 L, 780 mol). The reaction was stirred at room temperature for 5 hours and then at 115°C for 6 hours. The reaction was cooled to room temperature and diluted with DCM (686 L). To this solution was added water (508 L) and cooled to 0°C followed by dropwise addition of aqueous 30% NaOH while maintaining the temperature <20°C under pH=9. The mixture was filtered through diatomaceous earth (14 Kg) followed by washing the diatomaceous earth with 3 x DCM (50 L). The organic layer was separated, washed with aqueous 25% NaCl (200 L) and concentrated under vacuum to a volume of 70 L. The product was crystallized by charging the solution with 3 x n-heptane (88 L) while concentrating the volume to 70 L after each addition of n-heptane. The solid was filtered and washed 3 x n-heptane (22 L). The solid was dried under vacuum at 45°C to yield 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (XXI) (9.8 Kg, 46.2 mol, 92.6% purity, 48.4% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.48 (s, 3H), 8.50-8.55 (m, 2H), , 13.42 (brs, 1H); ESIMS found C7H6BrN3 m/z 213.7 (M+H).
    • Step 5
  • To a solution of NaOH (27 Kg, 675 mol) in water (617 L) was added 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (XXI) (9.8 Kg, 46.2 mol). The solution was heated at 90°C for 3 hours under nitrogen before adding a solution of KMnO4 (53.6 Kg, 339 mol) in water (870 L) slowly over 2 hours. The reaction was heated at 95°C for 5 hours under nitrogen. The solution was cooled to 75°C and filtered through diatomaceous earth (11 Kg) followed by washing the diatomaceous earth with water (150 L) heated at 75°C. The solution was cooled to 0°C under nitrogen before the pH was adjusted to 1 with aqueous 35% HC1 (∼75 L). The solution was warmed to room temperature before adding n-BuOH (473 L) which was stirred for 25 min and then the organic layer was separated. n-BuOH (473 L) was again added to the aqueous layer, stirred for 25 min and separated. The combined organic phases were concentrated under vacuum to a volume of ∼54 L. The n-BuOH was removed by adding to the solution 9 x n-heptane (78 L) dropwise over 1 hour and then concentrating the volume to ∼54 L after each addition of n-heptane. The solid was filtered and washed 3 x n-heptane (17 L). The solid was dried under vacuum at 45°C to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) (3.2 Kg, 13.2 mol, 64.4% purity, 29.0% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.57 (d, J=2.4Hz, 1H), 8.71 (d, J=2Hz, 1H), 13.45 (brs, 1H), 14.65 (s, 1H); ESIMS found C7H4BrN3O2 m/z 243.8 (M+H).
    • Step 6
  • To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) (1.6 Kg, 6.6 mol) in anhydrous MeOH (32 L) was added H2SO4 (160 mL). The reaction was slowly heated to 70°C and stirred for 20 hours. The solution was concentrated under vacuum to a volume of 1.6 L. The residue was partitioned between DCM (120 L) and aqueous 10% NaHCO3 (32 L). The organic phase was separated and washed with aqueous 25% NaCl (32 L), dried over Na2SO4 and concentrated to a volume of 4.8 L. The product was crystallized by charging the solution with 3 x n-heptane (8 L) while concentrating the volume to 4.8 L after each addition of n-heptane. The solid was filtered and dried under vacuum at 50°C to produce methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (1.53 Kg, 6.0 mol, 80.6% purity, 90.4% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 3.95 (s, 3H), 8.62 (d, J=2Hz, 1H), 8.73 (d, J=2.4Hz, 1H), 14.78 (brs, 1H); ESIMS found C8H6BrN3O2 m/z 256.0 (M+H).
    • Step 7
  • To a solution of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (2.92 Kg, 11.4 mol) in anhydrous DCM (88 L) was added TEA (2.38 L, 17.1 mol). The solution was cooled to 0°C before adding dropwise a solution of TrCl (4.0 Kg, 14.3 mol) in anhydrous DCM (51 L). The solution was warmed to room temperature and stirred for 20 hours. The reaction was then washed once with water (29 L), once with aqueous 25% NaCl (29 L), dried over Na2SO4 and concentrated to a volume of 3.0 L to give methyl 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XXII) (5.69 Kg, 11.4 mol, 77.3% purity, 99.5% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 3.91 (s, 3H), 7.19 (d, J=8.4Hz, 5H), 7.21-7.32 (m, 10H), 8.45 (d, J=2.4Hz, 1H), 8.61 (d, J=2Hz, 1H); ESIMS found C27H20BrN3O2 m/z 520.0 (M+Na).
    • Step 8
  • To a solution of methyl 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XXII) (4.16 Kg, 8.3 mol) in anhydrous THF (62 L) cooled to 10°C was added anhydrous EtOH (0.97 L, 16.6 mol) and LiBH4 (271 g, 12.5 mol). The reaction was warmed to room temperature and stirred for 24 hours. The solution was concentrated under vacuum to a volume of 4 L then taken up in DCM (80 L). The pH was then adjusted to 8.0 by dropwise addition of aqueous 0.4N HCl (∼280 L). The organic layer was separated and washed with aqueous 25% NaCl (28 L) and then concentrated under vacuum to a volume of 4 L to produce (5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (XXIII) (3.9 Kg, 8.3 mol, 82.3% purity, 100% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 4.70 (d, J=6Hz, 2H), 5.49 (t, J=6Hz, 1H), 7.19 (d, J=7.2Hz, 5H), 7.20-7.35 (m, 10H), 8.31 (d, J=2.4Hz, 1H), 8.51 (d, J=2.4Hz, 1H); ESIMS found C26H20BrN3O m/z 492.0 (M+Na).
    • Step 9
  • To a solution of (5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (XXIII) (4.05 Kg, 8.6 mol) in DCM (97 L) was added a solution of KBr (205 g, 1.72 mol) in water (4 L). The solution was cooled to 0°C before adding TEMPO (107.5 g, 688 mmol) and stirring for 30 min. To this solution was added a solution of KHCO3 (10.8 Kg, 107.4 mol) and aqueous 7% NaClO (13.4 L) in water (40 L). The reaction was stirred at 0°C for 18 hours. A solution of Na2S2O3*5H2O (1.4 Kg, 5.7 mol) in water (9.1 L) was added dropwise to the reaction at 0°C and stirred for 30 min. The aqueous layer was then separated and washed with DCM (48 L). The combined organic phases were washed with aqueous 25% NaCl (48 L), dried over Na2SO4, filtered and concentrated under vacuum. The residue was co-evaporated with 3 x MeOH (20 L) and the solid was washed with 2 x n-heptane (8 L). The solid was dried under vacuum at 45°C to give 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XXIV) (3.25 Kg, 6.94 mol, 92.3% purity, 80.6% assay yield). 1H NMR (CDCl3, 400 MHz) δ ppm 7.19 (d, J=6Hz, 5H), 7.22-7.34 (m, 10H), 8.28 (d, J=2.4Hz, 1H), 8.70 (d, J=2.4Hz, 1H), 10.07 (s, 1H); ESIMS found C26H18BrN3O m/z 490.0 (M+Na).
  • Preparation of intermediate N-(5-bromopyridin-3-yl)-2,2,2-trifluoroacetamide (XXVI) is depicted below in Scheme 5.
    Figure imgb1056
    • Step 1
  • To a solution of 5-bromopyridin-3-amine (XXV) (1.0 g, 5.78 mmol) in dry THF (20 mL) under argon was added TEA (0.826 mL, 6.35 mmol) and dropwise trifluoroacetic anhydride (0.902 mL, 6.35 mmol). The solution was stirred at room temperature for 3 h. The reaction was poured into ice water, basified by saturated aqueous NaHCO3, and then extracted with EtOAc. The combined organic phases were dried over MgSO4, concentrated and concentrated under vacuum to yield N-(5-bromopyridin-3-yl)-2,2,2-trifluoroacetamide (XXVI) as an off-white solid (1.5 g, 5.60 mmol, 96% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 8.36 (t, J=2Hz, 1H), 8.58 (d, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 11.57, (brs, 1H); ESIMS found C7H4BrF3N2O m/z 269.0 (M+H).
  • The following intermediate was prepared in accordance with the procedure described in the above Scheme 5.
    Figure imgb1057
  • tert-Butyl 5-bromopyridin-3-ylcarbamate (XXVII): Brown viscous oil (421 mg, 1.54 mmol, 23% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.48 (s, 9H), 8.17-8.18 (m, 1H), 8.29 (d, J=2Hz, 1H), 8.56 (d, J=2Hz, 1H), 9.82 (s, 1H); ESIMS found C10H13BrN2O2 m/z 273 (M+H).
  • Preparation of intermediate N-(5-bromopyridin-3-yl)pivalamide (XXIX) is depicted below in Scheme 6.
    Figure imgb1058
    • Step 1
  • To a solution of 3-amino-5-bromo pyridine (XXV) (1.0 g, 5.78 mmol) in dry pyridine (10 mL) was added pivaloyl chloride (XXVIII) (769 mg, 6.38 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was poured into an ice water/saturated aqueous NaHCO3 mixture and stirred for 30 min. The precipitate was filtered, washed with cold water and dried at room temperature to yield N-(5-bromopyridin-3-yl)pivalamide (XXIX) as an off-white solid (1.082 g, 4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.23 (s, 9H), 8.37 (d, J=2Hz, 1H), 8.39 (t, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS found C10H13BrN2O m/z 257.0 (M+H).
  • The following intermediates were prepared in accordance with the procedure described in the above Scheme 6.
    Figure imgb1059
  • N-(5-Bromopyridin-3-yl)isobutyramide (XXX): Off-white solid, (71% yield). 1H NMR (CDCl3) δ ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C9H11BrN2O m/z 243.05(M+H).
    Figure imgb1060
  • N-(5-Bromopyridin-3-yl)propionamide (XXXI): Off white solid (92% yield). 1H NMR (DMSO-d6) δ ppm 1.09 (t, J=7.54 Hz, 3H), 2.36 (q, J=7.54 Hz, 2H), 8.36 (m, 2H), 8.65 (d, J=2.07 Hz, 1H), 10.26 (s, 1H); ESIMS found C8H9BrN2O m/z 231 (M+H).
    Figure imgb1061
  • N-(5-Bromopyridin-3-yl)butyramide (XXXII): Yellow solid (2.1 g, 8.64 mmol, 88.8% yield). ESIMS found C9H11BrN2O m/z 243 (M+H).
    Figure imgb1062
  • N-(5-Bromopyridin-3-yl)pentanamide (XXXIII): Yellow solid (2.0 g, 7.78 mmol, 85.3% yield). ESIMS found C10H13BrN2O m/z 257 (M+H).
    Figure imgb1063
  • N-(5-Bromopyridin-3-yl)-3-methylbutanamide (XXXIV): Off white solid, (67% yield), 1H NMR (CDCl3, 500 MHz) δ ppm 8.55-8.42 (m, 3H), 7.62 (s, 1H), 2.31-2.18 (m, 3H), 1.02-1.01 (d, J = 6Hz, 6H); ESIMS found C10H13BrN2O m/z 258.80 (M+H).
    Figure imgb1064
  • N-(5-Bromopyridin-3-yl)-3,3-dimethylbutanamide (XXXV): Yellow solid (1.7 g, 6.27 mmol, 78.6% yield). ESIMS found C11H15BrN2O m/z 271 (M+H).
    Figure imgb1065
  • N-(5-Bromopyridin-3-yl)-2-phenylacetamide (XXXVI): White solid (2.5 g, 8.59 mmol, 77.9% yield). ESIMS found C13H11BrN2O m/z 291 (M+H).
    Figure imgb1066
  • N-(5-Bromopyridin-3-yl)benzamide (XXXVII): White solid (2.7 g, 9.74 mmol, 60% yield). ESIMS found C12H9BrN2O m/z 277 (M+H).
    Figure imgb1067
  • N-(5-Bromopyridin-3-yl)cyclopropanecarboxamide (XXXVIII): Off-white solid, (83% yield), 1H NMR (CDCl3, 500 MHz) δ ppm 8.46-8.39 (m, 3H), 7.54 (bs, 1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMS found for C9H9BrN2O m/z 240.9 (M+H).
    Figure imgb1068
    Figure imgb1069
  • N-(5-Bromopyridin-3-yl)cyclobutanecarboxamide (XXXIX): Yellow solid (2.1 g, 6.27 mmol, 86.6% yield). ESIMS found C10H11BrN2O m/z 255 (M+H).
    Figure imgb1070
  • N-(5-Bromopyridin-3-yl)cyclopentanecarboxamide (XL): Yellow solid (1.9 g, 7.06 mmol, 80.2% yield). ESIMS found C11H13BrN2O m/z 269 (M+H).
    Figure imgb1071
  • N-(5-bromopyridin-3-yl)cyclohexanecarboxamide (XLI): Yellow solid (2.0 g, 7.06 mmol, 84.3% yield). ESIMS found C12H15BrN2O m/z 283 (M+H).
  • Preparation of intermediate 5-bromo-N,N-dimethylpyridin-3-amine (XLIII) is depicted below in Scheme 7.
    Figure imgb1072
    • Step 1
  • To a solution of 3,5-dibromopyridine (XLII) (2.37 g, 10.0 mmol) in dry DMF (20.0 mL) was added K2CO3 (4.5 g, 33 mmol) and dimethylamino hydrochloride (1.79 g, 22 mmol). The mixture was heated overnight at 200°C in a sealed tube. The solution was cooled to room temperature and excess DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic phase was separated. The aqueous phase was washed with EtOAc and the combined organic phases were dried over MgSO4, and concentrated to afford 5-bromo-N,N-dimethylpyridin-3-amine (XLIII) as an off-white solid (1.78g, 8.85 mmol, 88% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.94 (s, 6H), 7.25 (t, J=2Hz, 1H), 7.91 (d, J=2Hz, 1H), 8.07 (d, J=2Hz, 1H); ESIMS found C7H9BrN2 m/z 201.1 (M+H).
  • The following intermediates were prepared in accordance with the procedure described in the above Scheme 7.
    Figure imgb1073
  • N1-(5-bromopyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine (XLIV): Brown viscous oil (326 mg, 1.33 mmol, 14% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.17 (s, 6H), 2.42 (t, J=6.4Hz, 2H), 3.08-3.12 (m, 2H), 6.03 (t, J=5.2Hz, 1H), 7.12-7.13 (m, 1H), 7.78 (d, J=2Hz, 1H), 7.97 (d, J=2Hz, 1H); ESIMS found C9H14BrN3 m/z 244 (M+H).
    Figure imgb1074
  • 1-(5-bromopyridin-3-yl)-4-methylpiperazine (XLV): Brown viscous oil (815 mg, 3.18 mmol, 28% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.21 (s, 3H), 2.41-2.43 (m, 4H), 3.22-3.24 (m, 4H), 7.51-7.52 (m, 1H), 8.02 (d, J=2Hz, 1H), 8.28 (d, J=2Hz, 1H); ESIMS found C10H14BrN3 m/z 256 (M+H).
  • Preparation of intermediate 5-bromo-N-isopropylpyridin-3-amine (XLVI) is depicted below in Scheme 8.
    Figure imgb1075
    • Steps 1
  • To a solution of 5-bromopyridin-3-amine (XXV) (535 mg, 3.09 mmol) in MeOH (62 mL) was added acetone (296 µL, 4.02 mL). The pH was adjusted to 4 using HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% hexane → 90:10 hexane:EtOAc) to produce 5-bromo-N-isopropylpyridin-3-amine (XLVI) as an oil which slowly solidified into an off-white solid (309 mg, 1.44 mmol, 47% yield). 1H NMR (DMSO-dδ, 500 MHz) δ ppm 1.12 (d, J=6.3Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9Hz, 1H), 7.05-7.06 (m, 1H), 7.75 (d, J=2Hz, 1H), 7.90 (d, J=2Hz, 1H); ESIMS found C8H11BrN2 m/z 215 (M+H).
  • Preparation of intermediate 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XLVIII) is depicted below in Scheme 9.
    Figure imgb1076
    • Steps 1
  • Preparation of 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XLVIII) was performed following the procedure listed in Scheme 6, Step 1. Brown oil (1.20 g, 5.59 mmol, 45% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=1.1Hz, 1H), 8.59 (d, J=2.2Hz, 1H); ESIMS found C8H11BrN2 m/z 215 (MBr79+H) and 217 (MBr81+H).
  • Preparation of intermediate N-(3-bromo-5-fluorobenzyl) methanesulfonamide (L) is depicted below in Scheme 10.
    Figure imgb1077
    • Steps 1
  • Preparation of 3-bromo-5-fluorobenzaldehyde (XLIX) (2.03 g, 10.0 mmol) in DCE (50 mL) was added methanesulfonamide (1.43 g, 15.0 mmol) and TEA (2.79 mL, 20.0 mmol). The solution was stirred for a few minutes before NaBH(OAc)3 (3.00 g, 14.1 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4 and evaporated under vacuum to give N-(3-bromo-5-fluorobenzyl)methanesulfonamide (L) as a clear oil (2.65 g, 9.39 mmol, 99% yield). ESIMS found C8H9BrFNO2S m/z 282 (M+H).
  • The following intermediates were prepared in accordance with the procedure described in the above Scheme 9 or Scheme 10.
    Figure imgb1078
  • 3-Bromo-5-(pyrrolidin-1-ylmethyl)pyridine (LI): Golden liquid (1.35 g, 97% yield). 1H NMR (DMSO-d6) 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H), 3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, J=2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for C10H13BrN2 m/z 242 (M+H).
    Figure imgb1079
  • 3-Bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridine (LII): Brown oil (6.4 g, 81% yield). ESIMS found for C10H11BrF2N2 m/z 277.0 (M+H).
    Figure imgb1080
  • 3-Bromo-5-(piperidin-1-ylmethyl)pyridine (LIII): Brown liquid (13.1 g, 94% yield). 1H NMR (DMSO-d6) 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H), 2.31-2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for C11H15BrN2 m/z 257 (M+H).
    Figure imgb1081
  • N-((5-Bromopyridin-3-yl)methyl)ethanamine (LIV): Golden liquid (1.29 g, 6.00 mmol, 60% yield). ESIMS found for C8H11BrN2 m/z 215 (M+H).
    Figure imgb1082
  • N-Benzyl-1-(5-bromopyridin-3-yl)methanamine (LV): Golden liquid (77 mg, 0.28 mmol, 25% yield). ESIMS found for C13H13BrN2 m/z 277 (M+H).
  • Preparation of intermediate tert-butyl (5-bromopyridin-3-yl)methyl (cyclopentylmethyl)carbamate (LX) is depicted below in Scheme 11.
    Figure imgb1083
    • Step 1
  • To a solution of 5-bromonicotinaldehyde (XLVII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (5-bromopyridin-3-yl)methanol (LVI) (1.8 g, 9.57 mmol, 90.0% yield) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO m/z 188 (M+H).
    • Step 2
  • To a stirred solution of (5-bromopyridin-3-yl)methanol (LVI) (1.60 g, 8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh3 (3.33 g, 12.75 mmol, 1.5 eq) in anhydrous THF (15 mL) was added DEAD (2.21 g, 12.75 mmol, 1.5 eq) dropwise at 0°C under N2. Then the reaction mixture was stirred at room temperature for 6 h. The mixture was washed with saturated NaHCO3 solution (15 mL), water (15 mL) and brine (15 mL) subsequently. The organic layers were dried over MgSO4, concentrated under reduced pressure, the resultant residue was purified by flash chromatography on silica gel (PE:EtOAc = 4:1) to give 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LVII) (2.5 g, 7.88 mmol, 82.3% yield) as a white solid. ESIMS found for C14H9BrN2O2 m/z 317 (M+H).
    • Step 3
  • A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LVII) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6 eq) in EtOH (20 mL) was heated at 70°C for 3 h. The mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo, the crude product was dissolved in IN HCl solution (15 mL) and concentrated to dryness, then it was washed with acetone (10 mL x 3), the precipitate was collected by filtration, dried in vacuo to give (5-bromopyridin-3-yl)methanamine (LVIII) (1.3 g, 6.95 mmol, 97.7% yield) as a white solid. 1H NMR (D2O, 500 MHz) δ ppm 4.34 (s, 2H), 8.56 (s, 1H), 8.75 (d, J=1.2Hz, 1H), 8.91 (d, J=1.6Hz, 1H). ESIMS found for C6H7BrN2 m/z 187 (M+H).
    • Step 4
  • A solution of (5-bromopyridin-3-yl)methanamine (LVIII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LIX) (1.23 g, 4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C12H17BrN2 m/z 269 (M+H).
    • Step 5
  • To a solution of 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl) methanamine (LIX) (1.00 g, 3.7 mmol, 1 eq) and TEA (0.93 g, 9.2 mmol, 2.5 eq) in DCM (20 mL) was added portionwise (Boc)2O (0.85 g, 4.0 mmol, 1.1 eq) at 0°C, the reaction mixture was stirred at room temperature for 1 h. The mixture was washed with water (10 mL), brine (10 mL), the organic layer was separated, dried over MgSO4 and concentrated in vacuo to give tert-butyl (5-bromopyridin-3-yl)methyl (cyclopentylmethyl)carbamate (LX) (1.25 g, 3.38 mmol, 91.9% yield) as a white solid. ESIMS found for C17H25BrN2O2 m/z 369 (M+H).
  • Preparation of intermediate 1-(3-bromo-5-fluorophenyl)-4-methylpiperazine (LXII) is depicted below in Scheme 12.
    Figure imgb1084
    • Step 1
  • To a solution of 1,3-dibromo-5-fluorobenzene (LXI) (2.0 g, 7.88 mmol) in toluene (20 ml) was added potassium t-butoxide (2.65 g, 23.6 mmol) and 1-methylpiperazine (1.75 mL, 15.8 mmol). The reaction was heated at 105°C overnight. The toluene was removed under vacuum and the residue was dissolved in water and extracted with EtOAc. The organic phase was separated, washed with brine, dried over MgSO4 and concentrated to dryness. The crude product was purified on a silica gel column (1:99 MeOH:CHCl3 → 7:93 MeOH:CHCl3) to produce 1-(3-bromo-5-fluorophenyl)-4-methylpiperazine (LXII) as an orange oil (800 mg, 2.93 mmol, 37.2% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.20 (s, 3H), 2.39 (t, J=5Hz, 4H), 3.33 (t, J=5Hz, 4H), 6.74-6.81 (m, 2H), 6.91 (s, 1H); ESIMS found for C11H14BrFN2 m/z 273 (M+H).
  • The following intermediates were prepared in accordance with the procedure described in the above Scheme 12.
    Figure imgb1085
  • N1-(3-Bromo-5-fluorophenyl)-N2,N2-dimethylethane-1,2-diamine (LXIII) as an orange oil (800 mg, 3.06 mmol, 38.9% yield). 1H NMR (DMSO-d6) δ ppm 1.28 (s, 6H), 2.39 (t, J=4Hz, 2H), 3.07 (q, J=6Hz, 2H), 6.10 (t, J=5Hz, 1H), 6.38 (td, J=12Hz, J=2Hz, 1H), 6.51 (td, J=8.6Hz, J=2Hz, 1H), 6.61 (t, J=2Hz, 1H); ESIMS found C10H14BrFN2 m/z 262.9 (M+H81Br).
    Figure imgb1086
  • 4-(3-Bromo-5-fluorophenyl)morpholine (LXIV) as a yellow oil (1.14 g, 4.38 mmol, 55.6% yield). 1H NMR (DMSO-d6) δ ppm 3.16 (t, J=5Hz, 4H), 3.70 (t, J=5Hz, 4H), 6.79 (td, J=12.8Hz, J=2Hz, 1H), 6.83 (td, J=8Hz, J=2Hz, 1H), 6.93 (s, 1H); ESIMS found C10H11BrFNO m/z 261.8 (M+H81Br).
    Figure imgb1087
  • 1-(3-Bromo-5-fluorophenyl)-4-isopropylpiperazine (LXV) as a light yellow oil (200 mg, 0.66 mmol, 34.1% yield). ESIMS found C13H18BrFN2 m/z 301.1 (M+H79Br).
    Figure imgb1088
  • 1-(3-Bromo-5-fluorophenyl)-4-methylpiperidine (LXVI) as a brown solid (870 mg, 3.20 mmol, 40.6% yield). 1H NMR (DMSO-d6) δ ppm ; ESIMS found C12H15BrFN m/z 272.0 (M+H79Br).
    Figure imgb1089
  • tert-Butyl 4-(3-bromo-5-fluorophenyl)piperazine-1-carboxylate (LXVII) as a yellow oil (232 mg, 0.65 mmol, 16.4% yield). ESIMS found C15H20BrFN2O2 m/z 361.0 (M+H81Br).
  • Preparation of intermediate 5'-fluoro-3,3'-bipyridine-4,5-diamine (LXXII) is depicted below in Scheme 13.
    Figure imgb1090
    • Step 1
  • A mixture of 3-nitropyridin-4-amine (LXVIII) (10 g, 71.88 mmol) and acetic acid (100 ml) was added to a sealed tube followed by addition of NaOAc (29.50g, 359 mmol) and dropwise addition of bromine (4.43 ml 86.3 mmol) under stirring. The sealed tube was heated at 100°C for overnight. The reaction mixture was concentrated under vacuum to obtain a solid which was dissolved in water, basified with saturated aqueous NaHCO3 and extracted with DCM. The combined organic extracts were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (LXIX) as a yellow solid (13.7 g, 62.8 mmol, 87% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 8.58 (s, 1H), 9.19 (s, 1H); ESIMS found for C5H4BrN3O2 m/z 218.1 (M+H).
    • Step 2
  • A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (790 mg, 3.62 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (LXX) (1.01 g, 4.35 mmol), K3PO4 (1.15 g, 5.44 mmol), water (10 mL) and DMF (10 mL) was degassed with argon thrice. Pd(PPh3)4 (209 mg, 0.18 mmol) was added to the reaction and the solution was heated at 90°C for 4 h. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3 → 1.5:98.5 MeOH[7N NH3]:CHCl3) to give 5'-fluoro-5-nitro-3,3'-bipyridin-4-amine (LXXI) as a yellow solid (626 mg, 2.67 mmol, 74% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.62 (brs, 2H), 7.86-7.89 (m, 1H), 8.15 (s, 1H), 8.47-8.48 (m, 1H), 8.67 (d, J=2.7Hz, 1H), 9.07 (s, 1H); ESIMS found C10H7FN4O2 m/z 235 (M+H).
    • Step 3
  • To a solution of 5'-fluoro-5-nitro-3,3'-bipyridin-4-amine (LXXI) (621 mg, 2.65 mmol) in EtOH (18 mL) was added 10% Pd/C (93 mg, 15% by wt). The solution was purged with hydrogen and stirred for overnight at room temperature under hydrogen. The suspension was filtered through Celite and concentrated under vacuum. The crude product was purified through a silica gel column (100% CHCl3 → 3:97 MeOH[7N NH3]:CHCl3) to produce 5'-fluoro-3,3'-bipyridine-4,5-diamine (LXXII) as an off-white solid (542 mg, 2.65 mmol, 100% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 4.78 (brs, 2H), 5.28 (brs, 2H), 7.46 (s, 1H), 7.70 (s, 1H), 7.73-7.76 (m, 1H), 8.44-8.45 (m, 1H), 8.56 (d, J=2.8Hz, 1H); ESIMS found C10H9FN4 m/z 205 (M+H).
  • Preparation of intermediate 3,3'-bipyridine-4,5-diamine (LXXIV) is depicted below in Scheme 14.
    Figure imgb1091
    • Step 1
  • A mixture of 3-nitropyridin-4-amine (LXVIII) (10 g, 71.94 mmol) and acetic acid (120 mL) was added to a sealed tube followed by addition of NaOAc (29.50g, 93.52mmol) and dropwise addition of bromine (4.7ml 359.7 mmol) under stirring. The sealed tube was heated at 100°C for 28 h until TLC showed consumption of starting material. The reaction mixture was concentrated to obtain a solid which was dissolved in water, basified with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (LXIX) as a yellow solid (12 g, 55 mmol, 77% yield). 1H NMR (DMSO-d6) δ ppm 9.19 ( s, 1H), 8.58 (s, 1H); ESIMS found for C5H4BrN3O2 m/z 217, 219 (M+, M+2).
    • Step 2
  • A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na2CO3 solution (78 ml) and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh3)2Cl2 (927 mg, 5 mmol%) was added to the reaction and the solution was refluxed for 15h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite® and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc → 2:98 MeOH:DCM) to give 5-nitro-3,3'-bipyridin-4-amine (LXXIII) as a yellow solid (5 g, 23.1 mmol, 87% yield). 1H NMR (CDCl3, 500 MHz,) δ ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H),7.52-7.48 (m, 1H). ESIMS found C10H8N4O2 m/z 216.95 (M+H).
    • Step 3
  • To a solution of 5-nitro-3,3'-bipyridin-4-amine (LXXIII) (5 g, 23 mmol) in MeOH (20 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 15 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 3,3'-bipyridine-4,5-diamine (LXXIV) as off white solid (3.3 g, 17.7 mmol, 76% yield). 1H NMR (DMSO-d6, 500 MHz,): δ ppm 8.63-8.53 (m, 1H), 7.90-7.83 (m, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.48-7.43 (m, 2H), 6.13 (bs, 2H), 5.31 (bs, 2H). ESIMS found C10H10N4 m/z 187.10 (M+H).
  • The following intermediates were prepared in accordance with the procedure described in the above Scheme 13 or Scheme 14.
    Figure imgb1092
  • 5-(3-Fluorophenyl)pyridine-3,4-diamine (LXXV) as a brown solid (2.03 g, 9.99 mmol, 50% yield). 1H NMR (DMSO-d6) δ ppm 7.16-7.27 (m, 2H), 4.86 (brs, 2H), 5.34 (brs, 2H), 7.45-7.53 (m, 3H), 7.70 (s, 1H); ESIMS found C11H10FN3 m/z 203.6 (M+H).
    Figure imgb1093
  • 5-(4-Fluorophenyl)pyridine-3,4-diamine (LXXVI): Light yellow solid, (97% yield). ESIMS found C11H10FN3 m/z 204.3 (M+H).
    Figure imgb1094
  • 5-(2-Fluorophenyl)pyridine-3,4-diamine (LXXVII): Light red solid, (44% yield). ESIMS found C11H10FN3 m/z 204.4 (M+H).
    Figure imgb1095
  • 3,4'-Bipyridine-4,5-diamine (LXXVIII): Light tan solid, (84% yield). ESIMS found C10H10N4 m/z 187.0 (M+H).
    Figure imgb1096
  • 2,3'-Bipyridine-4',5'-diamine (LXXIX): Tan amorphous solid, (76% yield). ESIMS found C10H10N4 m/z 187.0 (M+H).
    Figure imgb1097
  • 5-(Furan-3-yl)pyridine-3,4-diamine (LXXX): Light pink solid, (68% yield). ESIMS found C9H9N3O m/z 176.0 (M+H).
    Figure imgb1098
  • 5-(Thiophen-3-yl)pyridine-3,4-diamine (LXXXI): Light brown amorphous solid (100% yield). ESIMS found C9H9N3S m/z 192.0 (M+H).
    Figure imgb1099
  • 5-(Thiophen-2-yl)pyridine-3,4-diamine (LXXXII): White amorphous solid (1.257 g, 6.57 mmol, 100% yield). ESIMS found C9H9N3S m/z 192.2 (M+H).
    Figure imgb1100
  • 3-(Thiophen-2-yl)benzene-1,2-diamine (LXXXIII): Brown oil (925.5 mg, 4.86 mmol, 60.9% yield). ESIMS found C10H10N2S m/z 191.1 (M+H).
    Figure imgb1101
  • 2'-Fluorobiphenyl-2,3-diamine (LXXXIV): Black solid (0.8 g, 3.96 mmol, 92% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 3.99 (s, 2H), 4.62 (s, 2H), 6.32 (d, J=7.6Hz, 1H), 6.49 (t, J=7.6Hz, 1H), 6.60 (d, J=7.6Hz, 1H), 7.21-7.35 (m, 3H), 7.35-7.45 (m, 1H); ESIMS found for C12H11FN2 m/z 203 (M+H).
    Figure imgb1102
  • 3'-Fluorobiphenyl-2,3-diamine (LXXXV): White solid (2.0 g, 9.89 mmol, 81% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 4.16 (s, 2H), 4.64 (s, 2H), 6.38 (dd, J=7.6Hz, J=1.6Hz, 1H), 6.51 (t, J=7.6Hz, 1H), 6.60 (d, J=6Hz, 1H), 7.11-7.26 (m, 3H), 7.48 (q, J=6.4Hz, 1H); ESIMS found for C12H11FN2 m/z 203 (M+H).
    Figure imgb1103
  • 4'-Fluorobiphenyl-2,3-diamine (LXXXVI): White solid (2.4 g, 11.87 mmol, 98% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 4.07 (s, 2H), 4.60 (s, 2H), 6.34 (dd, J=7.6Hz, J=1.6Hz, 1H), 6.50 (t, J=7.6Hz, 1H), 6.58 (dd, J=7.6Hz, J=1.6Hz, 1H), 7.26 (t, J=7.6Hz, 2H), 7.40 (q, J=5.6Hz, 2H); ESIMS found for C12H11FN2 m/z 203 (M+H).
    Figure imgb1104
  • 3-(Pyridin-3-yl)benzene-1,2-diamine (LXXXVII): White solid (1.36 g, 7.34 mmol, 92.5% yield). 1H NMR (CDCl3, 400 MHz) δ ppm 1.57 (brs, 2H), 3.42 (brs, 2H), 6.66 (dd, J=6Hz, J=3.2Hz, 1H), 6.68-6.72 (m, 2H), 7.31 (dd, J=8Hz, J=4.8Hz, 1H), 7.71 (td, J=8Hz, J=2Hz, 1H), 8.54 (dd, J=4.8Hz, J=1.6Hz, 1H), 8.64 (d, J=1.6Hz, 1H); ESIMS found for C11H11N3 m/z 186 (M+H).
    Figure imgb1105
  • 3-(Thiophen-3-yl)benzene-1,2-diamine (LXXXVIII): White solid (1.2 g, 6.31 mmol, mmol, 94% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 4.19 (s, 2H), 4.59 (s, 2H), 6.47 (dd, J=4.8Hz, J=1Hz, 2H), 6.55 (q, J=4.8Hz, 1H), 7.24 (dd, J=4.8Hz, J=1Hz, 1H), 7.50 (t, J=1.6Hz, 1H), 7.63 (dd, J=4.8Hz, J=2.8Hz, 1H); ESIMS found for C10H10N2S m/z 191 (M+H).
    Figure imgb1106
    Figure imgb1107
  • 3-(Furan-3-yl)benzene-1,2-diamine (LXXXIX): White solid (1.3 g, 7.46 mmol, mmol, 85% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 4.24 (brs, 2H), 4.57 (brs, 2H), 6.46-6.50 (m, 1H), 6.50-6.56 (m, 2H), 6.72 (s, 1H), 7.74 (t, J=1.6Hz, 1H), 7.87 (s, 1H); ESIMS found for C10H10N2O m/z 175 (M+H).
  • Preparation of intermediate 3-(pyridin-4-yl)benzene-1,2-diamine (XCV) is depicted below in Scheme 15.
    Figure imgb1108
    • Step 1
  • To a solution of 2-bromoaniline (XC) (50 g, 0.29 mol, 1 eq) in acetic anhydride (265 mL) was added dropwise nitric acid (fuming) (36.75 mL, 0.93 mol, 3.2 eq) at 0°C and then stirred at that temperature, when the starting material was consumed, the mixture was filtered, the filtrate was poured into ice water. The aqueous phase was basified with aqueous solution of sodium bicarbonate to pH=7, then the mixture was extracted with EtOAc (30 mL x 3). The organic layers were combined, dried and concentrated in vacuo to give the N-(2-bromo-6-nitrophenyl)acetamide (XCI) (12.6 g, 48.6 mmol, 16.7% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.06 (s, 3H), 7.43 (t, J=8Hz, 1H), 7.94 (d, J=8Hz, 1H), 8.05 (d, J=8Hz, 1H); ESIMS found for C8H7BrN2O3 m/z 259 (M+H).
    • Step 2
  • A degassed mixture of N-(2-bromo-6-nitrophenyl)acetamide (XCI) (2.59 g, 10 mmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (XCII) (2.05 g, 10 mmol, 1.3 eq), Na2CO3 (2.12 g, 20 mmol, 2 eq) and Pd(PPh3)4 (1.16 g, 1 mmol, 0.1 eq) in a mixed solvent of DME (30 mL) and H2O (10 mL) was heated to reflux under nitrogen overnight, the mixture was poured onto water (40 ml) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, purification the resultant residue was purified by column chromatography (EtOAc:PE=1:4→100% EtOAc) to afford N-(2-nitro-6-(pyridin-4-yl)phenyl)acetamide (XCIII) (1.42 g, 5.52 mmol, 55% yield) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 1.92 (s, 3H), 7.46 (d, J=5.6Hz, 2H), 7.69 (t, J=8Hz, 1H), 7.80 (dd, J=7.6Hz, J=1.2Hz, 1H), 8.06 (dd, J=8Hz, J=1.6Hz, 1H), 8.73 (d, J=6Hz, 2H), 9.96 (s, 1H); ESIMS found for C13H11N3O3 m/z 258 (M+H).
    • Step 3
  • To a solution of N-(2-nitro-6-(pyridin-4-yl)phenyl)acetamide (XCIII) (3.94 g, 15 mmol, 1 eq) in methanol (20 mL) was added 2 N aqueous NaOH solution (50 mL) and the mixture was refluxed until the starting material was consumed completely, the precipitate was collected by filtration to afford the 2-nitro-6-(pyridin-4-yl)aniline (XCIV) (3.0 g, 13.9 mmol, 91% yield) as yellow solid. ESIMS found for C11H9N3O2 m/z 216 (M+H).
    • Step 4
  • To a solution of 2-nitro-6-(pyridin-4-yl)aniline (XCIV) (3 g, 14 mmol, 1 eq) in EtOAc (350 mL) was added Pd/C (0.3 g) and the mixture was stirred at room temperature under 1 atm of H2 atmosphere overnight, the mixture was filtered and concentrated in vacuo to give the product 3-(pyridin-4-yl)benzene-1,2-diamine (XCV) (2.4 g, 13.0 mmol, 93% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 4.35 (s, 2H), 4.75 (s, 2H), 6.45 (dd, J=7.6Hz, J=1Hz, 1H), 6.58 (t, J=7.6Hz, 1H), 6.67 (d, J=6.8Hz, 1H), 7.47 (d, J=6Hz, 2H), 8.65 (d, J=6Hz, 2H); ESIMS found for C11H11N3 m/z 186 (M+H).
  • Preparation of intermediate 3-(pyridin-2-yl)benzene-1,2-diamine 3HC1 (LXII) is depicted below in Scheme 16.
    Figure imgb1109
    • Step 1
  • To a solution of 2-bromopyridine (XCVI) (10 g, 63 mmol, 1.00 eq) in THF (150 mL) was added n-BuLi (25.3 mL, 63 mmol, 1.00 eq) and the mixture was stirred at -70°C for 30 min under nitrogen atmosphere. Then n-Bu3SnCl (21.7 g, 67 mmol, 1.06 eq) was added and the mixture was stirred at the same temperature for another 2 h. Saturated ammonium chloride solution (150 mL) was added to the solution and extracted with ethyl acetate (150 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude 2-(tributylstannyl)pyridine (XCVII) (25.9 g, 63 mmol, 100% yield) as a yellow oil. The crude product was used without further purification.
    • Step 2
  • A degassed mixture of N-(2-bromo-6-nitrophenyl)acetamide (XCI) (4.8 g, 19 mmol, 1.00 eq), 2-(tributylstannyl)pyridine (XCVII) (7.5 g, 20 mmol, 1.05 eq) and Pd(PPh3)4 (2.1 g, 1.8 mmol, 0.01 eq) in toluene (60 mL) was heated to reflux under nitrogen overnight. Saturated sodium bicarbonate solution (50 mL) was then added to the mixture and it was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, the residue was purified by column chromatography on silica gel (EtOAc:PE=1:2→100% EtOAc) to afford N-(2-nitro-6-(pyridin-2-yl)phenyl)acetamide (XCVIII) (4.4 g, 17.1 mmol, 92% yield) as a white-off solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 1.93 (s, 3H), 7.43-7.51 (m, 1H), 7.51-7.65 (m, 1H), 7.67 (d, J=7.6Hz, 1H), 7.97 (dd, J=7.6Hz, J=2.4Hz, 3H), 8.75 (d, J=4.4Hz, 1H), 10.52 (s, 1H); ESIMS found for C13H11N3O3 m/z 258 (M+H).
    • Step 3
  • To a solution of N-(2-nitro-6-(pyridin-2-yl)phenyl)acetamide (XCVIII) (4.41 g, 17 mmol, 1 eq) in MeOH (20 mL) was added 2N NaOH aqueous (50 mL) and the mixture was refluxed until the stirring material was consumed completely. The mixture was concentrated in vacuo to remove the MeOH and the precipitate was collected by filtration to afford 2-nitro-6-(pyridin-2-yl)aniline (XCIX) (2.4 g, 11.2 mmol, 65% yield) as a yellow solid. ESIMS found for C11H9N3O2 m/z 216 (M+H).
    • Step 4
  • To a solution of 2-nitro-6-(pyridin-2-yl)aniline (XCIX) (2.4 g, 0.01 mmol, 1 eq) in EtOAc (350 mL) was added Pd/C (1 g) and the mixture was stirred at room temperature overnight, filtered and then concentrated in vacuo, to give 3-(pyridin-2-yl)benzene-1,2-diamine (1.9 g, 10.3 mmol, 89% yield) as a yellow oil. ESIMS found for C11H11N3 m/z 186 (M+H).
    • Step 5
  • To a solution of 3-(pyridin-2-yl)benzene-1,2-diamine (1.86 g, 0.01 mmol) in EtOAc (200 mL) was added HC1 in EtOAc (40 mL) and the mixture was stirred at 0°C for 20 min. The precipitate was collected by filtration to give 3-(pyridin-2-yl)benzene-1,2-diamine-3HCl (C) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 6.89 (t, J=7.6Hz, 1H), 7.33 (brs, 1H), 7.51 (d, J=7.2Hz, 1H), 7.54-7.66 (m, 2H), 7.97 (d, J=8Hz, 1H), 8.16 (brs, 1H), 8.75 (brs, 1H).
  • Preparation of intermediate 5-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine-3,4-diamine (XLV) is depicted below in Scheme 17.
    Figure imgb1110
    • Step 1
  • A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3 → 3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H).
    • Step 2-3
  • A solution of 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) (528 mg, 1.84 mmol), bis(pinacolato)diboron (560 mg, 2.21 mmol), KOAc (541 mg, 5.51 mmol) and dry DMF (26 mL) was purged with argon. PdCl2(dppf)2 (90 mg, 0.11 mmol) was added to the reaction and purged again with argon. The solution was heated at 90°C for 2 h. Once TLC showed the disappearance of (CII), the solution was cooled to room temperature. To this solution was added K3PO4 (588 mg, 2.76 mmol), 3-bromo-5-nitropyridin-4-amine (LXIX) (400 mg, 1.84 mmol), Pd(PPh3)4 (106 mg, 0.09 mmol) and water (5 mL). The solution was purged with argon and heated at 90°C for 4 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned between CHCl3 and water. The aqueous phase was separated and washed 2x CHCl3. The combined organic phases were washed with brine, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% CHCl3 →2:98 MeOH[7N NH3]:CHCl3) to give 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-5-nitropyridin-4-amine (CIV) as a yellow amorphous solid (419 mg, 1.21 mmol, 42% yield for 2 steps). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.27-2.41 (m, 8H), 3.52 (s, 2H), 7.16-7.22 (m, 3H), 7.42 (brs, 2H), 8.11 (s, 1H), 9.04 (s, 1H); ESIMS found for C17H20FN5O2 mlz 346.0(M+H).
    • Step 4
  • To a solution of 3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl) phenyl)-5-nitropyridin-4-amine (CIV) (265 mg, 0.77 mmol) in MeOH (5 mL) was added 10% Pd/C (40 mg, 15% by wt). The solution was purged with hydrogen and stirred for 4 h at room temperature under hydrogen. The suspension was filtered through Celite and concentrated under vacuum to produce 5-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)pyridine-3,4-diamine (CV) as a tan solid (210 mg, 0.66 mmol, 86% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.32-2.40 (m, 8H), 3.51 (s, 2H), 4.71 (brs, 2H), 5.05 (brs, 2H), 7.06-7.10 (m, 2H), 7.14 (s, 1H), 7.43 (s, 1H), 7.67 (s, 1H); ESIMS found C17H22FN5 m/z 316 (M+H).
  • The following intermediates were prepared in accordance with the procedure described in the above Scheme 17.
    Figure imgb1111
  • 5-(3-((Dimethylamino)methyl)-5-fluorophenyl)pyridine-3,4-diamine (CVI): Light brown solid (551 mg, 2.11 mmol, 71% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.18 (s, 6H), 3.44 (s, 2H), 4.71 (brs, 2H), 5.04 (brs, 2H), 7.07-7.10 (m, 2H), 7.13 (s, 1H), 7.44 (s, 1H), 7.67 (s, 1H); ESIMS found C14H17FN4 m/z 261 (M+H).
    Figure imgb1112
  • 5-(3-fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)pyridine-3,4-diamine (CVII): Light brown solid (551 mg, 2.11 mmol, 71% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.69-1.71 (m, 4H), 2.45-2.48 (m, 4H), 3.63 (s, 2H), 4.71 (brs, 2H), 5.04 (brs, 2H), 7.05-7.07 (m, 1H), 7.09-7.11 (m, 1H), 7.14 (s, 1H), 7.43 (s, 1H), 7.67 (s, 1H); ESIMS found C16H19FN4 m/z 287 (M+H).
    Figure imgb1113
  • 5-(3-((diisopropylamino)methyl)-5-fluorophenyl)pyridine-3,4-diamine (CVIII): Light brown solid (551 mg, 2.11 mmol, 71% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.00 (d, J=6.6Hz, 12H), 2.99 (sep, J=6.6Hz, 2H), 3.67 (s, 2H), 4.71 (brs, 2H), 5.03 (brs, 2H), 6.99-7.01 (m, 1H), 7.13-7.15 (m, 1H), 7.22 (s, 1H), 7.43 (s, 1H), 7.67 (s, 1H); ESIMS found C18H25FN4 m/z 317 (M+H).
    Figure imgb1114
  • Preparation of 5'-(trifluoromethyl)-3,3'-bipyridine-4,5-diamine (CIX) was performed following the procedure listed in Scheme 11, Steps 2-4. Off-white solid (378 mg, 1.49 mmol, 98% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 4.78 (brs, 2H), 5.30 (brs, 2H), 7.46 (s, 1H), 7.72 (s, 1H), 8.13-8.14 (m, m, 1H), 8.86 (d, J=1.7Hz, 1H), 8.95 (d, J=1.1Hz, 1H); ESIMS found C11H9F3N4 m/z 255 (M+H).
    Figure imgb1115
  • Preparation of 5-(3-fluoro-5-morpholinophenyl)pyridine-3,4-diamine (CX) was performed following the procedure listed in Scheme 11, Steps 2-4. Yellow solid (156 mg, 0.54 mmol, 86% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.18 (t, J=5Hz, 4H), 3.72 (t, J=5Hz, 4H), 4.69 (s, 2H), 5.02 (s, 2H), 6.57 (d, J=9Hz, 1H), 6.70 (s, 1H), 6.76 (td, J=12Hz, J=2Hz, 1H), 7.45 (s, 1H), 7.73 (s, 1H); ESIMS found C15H17FN4O m/z 288.6 (M+H).
    Figure imgb1116
  • Preparation of 5-(3-fluoro-5-(4-methylpiperazin-1-yl)phenyl)pyridine-3,4-diamine (CXI) was performed following the procedure listed in Scheme 11, Steps 2-4. Amorphous solid (170 mg, 0.56 mmol, 98.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.22 (s, 3H), 2.44 (t, J=5Hz, 4H), 3.21 (t, J=5Hz, 1H), 4.90 (brs, 2H), 5.41 (brs, 2H), 6.55 (d, J=9Hz, 1H), 6.69 (s, 1H), 6.77 (d, J=13Hz, 1H), 7.12 (t, J=7Hz, 1H), 7.60-7.71 (m, 1H); ESIMS found C16H20FN5 m/z 302.0 (M+H).
    Figure imgb1117
  • Preparation of 5-(3-(2-(dimethylamino)ethylamino)-5-fluorophenyl) pyridine-3,4-diamine (CXII) was performed following the procedure listed in Scheme 11, Steps 2-4. Brown solid (148 mg, 0.51 mmol, 94.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.20 (s, 6H), 2.46 (t, J=7Hz, 2H), 3.12 (q, J=6Hz, 2H), 4.79 (s, 2H), 5.21 (s, 2H), 5.91 (t, J=5Hz, 1H), 6.28 (dd, J=9Hz, J=1Hz, 1H), 6.36 (t, J=2Hz, 1H), 6.37-6.42 (m, 1H), 7.46 (s, 1H), 7.64 (s, 1H); ESIMS found C15H20FN5 m/z 290.0 (M+H).
    Figure imgb1118
  • Preparation of N-(3-(4,5-Diaminopyridin-3-yl)-5-fluorobenzyl) methanesulfonamide (CXIII) was performed following the procedure listed in Scheme 11, Steps 2-4. Light tan solid (428.4 mg, 1.38 mmol, quantitative yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.92 (s, 3H), 4.24 (d, J=6.3Hz, 2H), 4.80 (s, 2H), 5.23 (s, 2H), 7.11-7.13 (m, 1H), 7.16-7.18 (m, 1H), 7.22 (s, 1H), 7.47 (s, 1H), 7.64 (d, J=6.3Hz, 1H), 7.68 (s, 1H); ESIMS found C13H15FN4O2S m/z 311 (M+H).
    Figure imgb1119
  • Preparation of 5-(3-fluoro-5-(4-isopropylpiperazin-1-yl)phenyl) pyridine-3,4-diamine (CXIV) was performed following the procedure listed in Scheme 11, Steps 2-4. Light yellow amorphous solid (100 mg, 0.30 mmol, 99% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.99 (d, J=6.5Hz, 6H), 2.52-2.58 (m, 4H), 2.67 (sep, J=6.5Hz, 1H), 3.14-3.23 (m, 4H), 4.74 (brs, 2H), 5.11 (s, 2H), 6.53 (d, J=9Hz, 1H), 6.67 (s, 1H), 6.74 (d, J=13Hz, 1H), 7.45 (brs, 1H), 7.66 (brs, 1H); ESIMS found C18H24FN5 m/z 330.0 (M+H).
    Figure imgb1120
  • Preparation of tert-butyl 4-(3-(4,5-diaminopyridin-3-yl)-5-fluorophenyl) piperazine-1-carboxylate (CXV) was performed following the procedure listed in Scheme 11, Steps 2-4. Light brown amorphous solid (376 mg, 0.97 mmol, 87.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.42 (s, 9H), 3.20 (t, J=5Hz, 4H), 3.44 (t, J=5Hz, 4H), 4.69 (s, 2H), 5.02 (s, 2H), 6.56 (d, J=9Hz, 1H), 6.71 (s, 1H), 6.77 (td, J=13Hz, J=2Hz, 1H), 7.44 (s, 1H), 7.66 (s, 1H); ESIMS found C20H26FN5O2 m/z 388.1 (M+H).
    Figure imgb1121
  • Preparation of 5-(3-fluoro-5-(4-methylpiperidin-1-yl)phenyl)pyridine-3,4-diamine (CXVI) was performed following the procedure listed in Scheme 11, Steps 2-4. Light brown amorphous solid (150 mg, 0.50 mmol, 99% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.93 (d, J=6.5Hz, 3H), 1.20 (dq, J=12Hz, J=4Hz, 2H), 1.46-1.58 (m, 1H), 1.67 (d, J= 11Hz, 2H), 2.71 (dt, J=12Hz, J=2Hz, 2H), 3.74 (d, J=12.7Hz, 2H), 4.68 (s, 2H), 5.00 (s, 2H), 6.48 (dd, J=8.7Hz, J=1Hz, 1H), 6.66 (s, 1H), 6.72 (td, J=13Hz, J=2Hz, 1H), 7.44 (s, 1H), 7.65 (s, 1H); ESIMS found C17H21FN4 m/z 301.0 (M+H).
  • Preparation of intermediate 5-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (CXVIII) is depicted below in Scheme 18.
    Figure imgb1122
    • Step 1
  • A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (618 mg, 2.83 mmol) in 1-methylpiperazine (1 mL, 8.51 mmol) was heated at 140°C overnight. The reaction was poured into an EtOAc/H2O mixture; the organic layer was separated, dried over MgSO4 and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3 → 3:97 MeOH(7N NH3):CHCl3) to give 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (CXVII) as a yellow solid (382 mg, 1.61 mmol, 56.7% yield). 1H NMR (CDCl3, 500 MHz,) δ ppm 2.20 (s, 3H), 2.35-2.37 (m, 4H), 4.52-3.54 (m, 4H), 5.96 (s, 1H), 7.42 (s, 2H), 8.78 (s, 1H); ESIMS found C10H15N5O2 m/z 238 (M+H).
    • Step 2
  • To a solution of 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (CXVII) (382 mg, 1.61 mmol) in MeOH (11 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 4 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 5-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (CXVIII) as purple solid (330 mg, 1.59 mmol, 99% yield). 1H NMR (DMSO-d6, 500 MHz,): δ 2.18 (s, 3H), 2.34-2.36 (m, 4H), 3.13-3.16 (m, 4H), 3.89 (s, 2H), 5.20 (s, 2H), 5.94 (s, 1H), 7.31 (s, 1H); ESIMS found C10H17N5 mlz 208 (M+H).
  • The following intermediates were prepared in accordance with the procedure described in the above Scheme 18.
    Figure imgb1123
  • 5-(Piperidin-1-yl)pyridine-3,4-diamine (CXIX): Purple solid, (83% yield). ESIMS found C10H16N4 m/z 193.1 (M+H).
    Figure imgb1124
  • 5-(Piperidin-1-yl)pyridine-3,4-diamine (CXX): Black solid (1.31 g, 6.35 mmol, 92% yield). 1H NMR (CDCl3, 400 MHz) δ ppm 2.30 (s, 3H), 3.30 (brs, 2H), 3.68 (brs, 2H), 6.46 (dd, J=7.2Hz, J=2Hz, 1H), 6.54-6.63 (m, 2H); ESIMS found for C11H18N4 m/z 207 (M+H).
  • Preparation of intermediate 3-(piperidin-1-yl)benzene-1,2-diamine (CXXIII) is depicted below in Scheme 19.
    Figure imgb1125
    • Step 1
  • To a solution of 3-chloro-2-nitroaniline (CXXI) (2.00 g, 11.6 mmol, 1 eq) and piperidine (2.95 g, 34.7 mmol, 3 eq) in DMF (60 ml) was added K2CO3 (4.78 g, 34.4 mmol, 3 eq) in one portion and the mixture was stirred at 120°C under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with saturated NaHCO3 solution (50 mL). The organic phases were dried over Na2SCO4 and concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (PE:EtOAc = 5:1→1:1) to give 2-nitro-3-(piperidin-1-yl)aniline (CXXII) (1.8 g, 8.14 mmol, 70.3% yield) as a black solid. ESIMS found for C11H15N3O2 m/z 222 (M+H).
    • Step 2
  • A mixture of 2-nitro-3-(piperidin-1-yl)aniline (CXXII) (1.64 g, 6.9mmol, 1 eq) and Pd/C (0.50 g) in MeOH (20 mL) was stirred at room temperature under 30 psi H2 overnight. After the starting material was consumed completely, the mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to give the 3-(piperidin-1-yl)benzene-1,2-diamine (CXXIII) (1.1 g, 5.75 mmol, 76% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ ppm 1.59 (brs, 2H), 1.73 (quin, J=5.6Hz, 4H), 2.84 (brs, 4H), 3.50 (brs, 4H), 6.52 (dd, J=6.4Hz, J=1.6Hz, 1H), 6.59-6.75 (m, 2H); ESIMS found for C11H17N3 m/z 192 (M+H).
  • Preparation of 4,5-diamino-N-ethylnicotinamide (LX) is depicted below in Scheme 20.
    Figure imgb1126
    • Step 1
  • To a solution of concentrated sulfuric acid (2 mL) was slowly added 2-aminobenzoic acid (CXXIV) (1.0 g, 7.24 mmol). A mixture of concentrated sulfuric acid (1.5 mL) and fuming nitric acid (1.5 mL) was then slowly added and the reaction was stirred at room temperature overnight. The reaction mixture was poured into crushed ice and treated with aqueous NH4OH until pH 3.0. The yellow-orange solid was washed with cold water and dried to produce 2-(nitroamino)benzoic acid (CXXV) as a yellow solid (1.0 g, 5.46 mmol, 75.4% yield). The crude product was used for the next step without further purification. ESIMS found for C7H6N2O4 m/z 183.9 (M+H).
    • Step 2
  • To a solution of concentrated sulfuric acid (2 mL) was slowly added 2-(nitroamino)benzoic acid (CXXV) (183 mg, 1.0 mmol). The mixture was stirred at 100°C for 1 h. The solution was cooled, poured into crushed ice and treated with aqueous NH4OH until pH 3.0 while maintaining the temperature under 20°C. The solid was washed with cold water and dried to produce 2-amino-3-nitrobenzoic acid (CXXVI) as a yellow solid (55 mg, 0.30 mmol, 30.2% yield). Used for the next step without further purification. 1H NMR (DMSO-d6, 500 MHz) δ ppm 8.50 (brs, 1H), 8.89 (s, 1H), 8.99 (brs, 1H), 9.14 (s, 1H), 13.88 (brs, 1H); ESIMS found for C7H6N2O4 m/z 184.1 (M+H).
    • Step 3
  • To a solution of 2-amino-3-nitrobenzoic acid (CXXVI) (366 mg, 2.0 mmol) in DCM (5 mL) and DMF (1 mL) was added ethylamine hydrochloride and EDC. The mixture was cooled to 0°C under argon before added DIPEA. The reaction was stirred at room temperature for 3 h. The solution was concentrated under vacuum, dissolved in water and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% CHCl3 → 5:95 MeOH[7N NH3]:CHCl3) to give 4-amino-N-ethyl-5-nitronicotinamide (CXXVII) as a yellow solid (200 mg, 0.95 mmol, 47.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.14 (t, J=7Hz, 3H), 3.28 (q, J=6 Hz, 2H), 8.97 (s, 1H), 9.06 (s, 1H).
    • Step 4
  • To a solution of 4-amino-N-ethyl-5-nitronicotinamide (CXXVII) (180 mg, 0.856 mmol) in MeOH (5 mL) was added 10% Pd/C (27 mg, 15% by wt). The solution was purged with hydrogen and stirred for 16 h at room temperature under hydrogen. The suspension was filtered through Celite and concentrated under vacuum. The residue was purified on a silica gel column (100% CHCl3 → 10:90 MeOH[7N NH3]:CHCl3) to produce 4,5-diamino-N-ethylnicotinamide (CXXVIII) as a dark yellow solid (80 mg, 0.44 mmol, 51.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.14 (t, J=7Hz, 3H), 3.92 (q, J=7Hz, 2H) 5.56 (brs, 2H), 6.60 (brs, 1H), 7.66 (s, 1H), 8.30 (s, 1H); ESIMS found C8H12N4O m/z 181 (M+H).
  • Preparation of intermediate 3-(4-methyl-imidazol-1-yl)-benzene-1,2-diamine (CXXX) is depicted below in Scheme 21.
    Figure imgb1127
    • Step 1
  • A solution of 3-chloro-2-nitro-aniline (CXXI) (1.0 g, 5.8 mmol), potassium carbonate (2.4 g, 17.4 mmol), and 4-methylimidazole in dry DMF was heated overnight at 120°C under nitrogen. The reaction was cooled and the solvent was evaporated in vacuo. The residue was suspended in a saturated NaHCO3 solution and extracted with CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography to provide 3-(4-methyl-imidazol-1-yl)-2-nitro-phenylamine (CXXIX). 1H NMR (CDCl3, 400 MHz) δ ppm 2.19 (s, 3H), 6.53 (m, 1H), 6.79 (m, 1H), 6.93 (m, 1H), 7.32 (m, 1H), 7.60 (m, 1H).
    • Step 2
  • To a solution of 3-(4-methyl-imidazol-1-yl)-2-nitro-phenylamine (CXXIX) in methanol was added with 5% Pd/C. The combination was stirred under a hydrogen filled balloon at 40°C for 6 hours. The solution was then filtered through a pad of Celite. The filtrate was concentrated in vacuo to get 3-(4-methyl-imidazol-1-yl)-benzene-1,2-diamine (CXXX). 1H NMR (CDCl3, 400 MHz) δ ppm 2.17 (s, 3H), 6.54 (m, 1H), 6.80 (m, 1H), 6.97 (m, 1H), 7.28 (m, 1H), 7.56 (m, 1H).
    • Example 1.
  • Preparation of 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (3) is depicted below in Scheme 22.
    Figure imgb1128
    • Step 1
  • To a heterogeneous solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (III) (328 mg, 1.05 mmol) and K3PO4 (334 mg, 1.57 mmol) in DMF (10 mL) and water (2 mL) was added pyridin-3-ylboronic acid (143 mg, 1.16 mmol). The solution was purged with argon by using argon/vacuum cycle (3x). Pd(PPh3)4 (36 mg, 0.03 mmol) was added to the solution and again purged with argon. The solution was heated at 90°C for 4 h under argon. The DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined EtOAc was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified through a silica gel column (10:90 EtOAc:hexane → 50:50 EtOAc:hexane) to produce 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo [3,4-b]pyridine-3-carbaldehyde (CXXXI) as an off-white waxy solid (283 mg, 0.92 mmol, 91% yield). 1H NMR (DMSO-d6) δ ppm 1.57-1.68 (m, 3H), 1.75-1.89 (m, 1H), 2.01-2.13 (m, 2H), 2.49-2.56 (m, 1H), 3.78 (dt, J=11Hz, J=4Hz, 1H), 3.94-4.03 (m, 1H), 6.25 (dd, J=10Hz, J=2Hz, 1H), 7.58-7.64 (m, 1H), 8.25 (td, J=8Hz, J=2Hz, 1H), 8.66 (dd, J=5Hz, J=2Hz, 1H), 8.77 (d, J=2Hz, 1H), 9.02 (d, J=2Hz, 1H), 9.09 (d, J=2Hz, 1H), 10.21 (s, 1H); ESIMS found for C17H16N4O2 m/z 309.4 (M+H).
    • Step 2-3
  • A solution of 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (CXXXI) (65 mg, 0.21 mmol), 5-(3-fluorophenyl)pyridine-3,4-diamine (LXXV) (45 mg, 0.22 mmol) and sulfur (7 mg, 0.22 mmol) in n-butanol (10 mL) was heated at reflux overnight. The solution was cooled to room temperature, filtered and the solvent was evaporated under reduced pressure to give crude 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (CXXXII). CXXXII was dissolved in dry DCM (5 mL) before adding triethylsilane (84 µL, 0.52 mmol) and TFA (2.5 mL). The reaction was stirred at room temperature for 2 h under argon. The solvent was evaporated under reduced pressure; the residue was taken up water (10 mL), and basified with 5N NH4OH. The precipitates were filtered, washed by cold water and dried under vacuum at room temperature. The crude product was suspended in DCM (10 mL), sonicated briefly and then heated to boiling for 5 min. The solution was cooled to room temperature and the solids were filtered, washed with DCM and dried under vacuum at room temperature to produce 3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (3) as a yellow solid (53 mg, 0.13 mmol, 62% yield). 1H NMR (DMSO-d6) δ ppm 7.25-7.34 (m, 1H), 7.54-7.65 (m, 2H), 8.11-8.21 (m, 1H), 8.23-8.30 (m, 1H), 8.37-8.50 (m, 1H), 8.63-8.70 (m, 1H), 8.70-8.80 (m, 1H), 9.02-9.09 (m, 2H), 9.09-9.15 (m, 1H), 13.94 (brs, 1H), 14.59 (s, 1H); ESIMS found for C23H14FN7 m/z 408.1 (M+H).
  • The following compounds were prepared in accordance with the procedure described in the above Example 1.
    Figure imgb1129
     N-Ethyl-2-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide 8.
  • Brown solid (4.4 mg, 0.01 mmol, 35.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.23-1.34 (m, 3H), 3.48-3.59 (m, 2H), 5.76 (s, 1H), 7.58 (q, J=5Hz, 1H), 8.27-8.33 (m, 1H), 8.67 (d, J=5Hz, 1H), 9.01 (s, 1H), 9.03 (s, 1H), 9.07 (s, 1H), 9.33 (brs, 1H), 14.19 (brs, 1H), 14.75 (brs, 1H); ESIMS found C20H16N8O m/z 385.0 (M+H).
    Figure imgb1130
     3-(7-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 10.
  • Off-white solid (62 mg, 0.12 mmol, 73% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.21 (brs, 3H), 2.30-2.47 (m, 8H), 3.59 (s, 2H), 7.21 (d, J=9Hz, 1H), 7.59 (dd, J=8Hz, J=5Hz, 1H), 8.13-8.29 (m, 2H), 8.25 (d, J=8Hz, 1H), 8.68 (dd, J=5Hz, J=1.4Hz, 1H), 8.75 (brs, 1H), 8.89 (brs, 1H), 9.04 (dd, J=9Hz, J=2Hz, 2H), 9.08 (s, 1H), 13.91 (brs, 1H), 14.61 (brs, 1H); ESIMS found C29H26FN9 m/z 520.3 (M+H).
    Figure imgb1131
     3-(7-(3-Fluoro-5-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 11.
  • Off-white solid (72 mg, 0.14 mmol, 75% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.16 (brs, 3H), 2.23-2.40 (m, 4H), 3.19-3.30 (m, 4H), 6.84 (d, J=12Hz, 1H), 7.54-7.65 (m, 2H), 7.79 (s, 1H), 8.21 (d, J=8Hz, 1H), 8.69 (d, J=2Hz, 2H), 8.73 (s, 1H), 8.87 (s, 1H), 8.97-9.05 (m, 2H), 13.86 (brs, 1H), 14.61 (brs, 1H); ESIMS found C28H24FN9 m/z 506.3 (M+H).
    Figure imgb1132
     N1-(3-Fluoro-5-(2-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-7-yl)phenyl)-N2,N2-dimethylethane-1,2-diamine 12.
  • Off-white solid (21 mg, 0.04 mmol, 50% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 6H), 2.40 (brs, 2H), 3.17 (t, J=6Hz, 2H), 5.94 (brs, 1H), 6.48 (d, J=12Hz, 1H), 7.32-7.47 (m, 2H), 7.58 (dd, J=8Hz, J=5Hz, 1H), 8.25 (d, J=8Hz, 1H), 8.64 (s, 1H), 8.68 (dd, J=5Hz, J=1.5Hz, 1H), 8.85 (s, 1H), 9.06 (d, J=2Hz, 2H), 9.11 (s, 1H), 13.83 (brs, 1H), 14.58 (brs, 1H); ESIMS found C27H24FN9 m/z 494 (M+H).
    Figure imgb1133
     4-(3-Fluoro-5-(2-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-7-yl)phenyl)morpholine 13.
  • Off-white solid (38 mg, 0.08 mmol, 77% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.14-3.21 (m, 4H), 3.51-3.59 (m, 4H), 6.86 (d, J=12Hz, 1H), 7.58 (dd, J=8Hz, J=5Hz, 1H), 7.63 (d, J=10Hz, 1H), 7.74 (s, 1H), 8.22 (d, J=8Hz, 1H), 8.68 (d, J=5Hz, 1H), 8.73 (s, 1H), 8.87 (s, 1H), 9.01 (d, J=2Hz, 2H), 9.04 (s, 1H), 13.87 (s, 1H), 14.61 (s, 1H); ESIMS found C27H21FN80 m/z 493.1 (M+H).
    Figure imgb1134
     1-(3-Fluoro-5-(2-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-7-yl)phenyl)-N,N-dimethylmethanamine 14.
  • Off-white solid (38 mg, 0.08 mmol, 62.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.10 (s, 6H), 3.51 (s, 2H), 7.20 (brd, 1H), 7.59 (dd, J=8Hz, J=5Hz, 1H), 8.13 (brd, 1H), 8.20-8.27 (m, 2H), 8.69 (d, J=3Hz, 1H), 8.75 (s, 1H), 8.89 (s, 1H), 9.03 (d, J=2Hz, 1H), 9.04 (d, J=2Hz, 1H), 9.06 (s, 1H), 13.90 (s, 1H), 14.62 (s, 1H); ESIMS found C26H21FN8 m/z 465.3 (M+H).
    Figure imgb1135
     3-(7-(3-Fluoro-5-(4-isopropylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-c] pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 15.
  • Off-white solid (41 mg, 0.08 mmol, 57.3% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.93 (brs, 6H), 2.32-2.41 (m, 4H), 2.51-2.60 (m, 1H), 3.13-3.23 (m, 4H), 6.84 (brd, 1H), 7.52-7.61 (m, 1H), 7.58 (dd, J=8Hz, J=5Hz, 1H), 7.77 (brs, 1H), 8.22 (brd, 1H), 8.68 (d, J=5Hz, 1H), 8.72 (s, 1H), 9.02 (d, J=2Hz, 1H), 9.02-9.06 (m, 2H), 13.87 (s, 1H), 14.61 (s, 1H); ESIMS found C30H28FN9 m/z 534.5 (M+H).
    Figure imgb1136
     3-(7-(3-Fluoro-5-(pyrrolidin-1-ylmethyl)phenyl)-3H-imidazo[4,5-c] pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 16.
  • Off-white solid (24 mg, 0.05 mmol, 33.5% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.54-1.67 (m, 4H), 2.33-2.47 (m, 4H), 3.69 (brs, 2H), 7.21 (brd, 1H), 7.59 (dd, J=8Hz, J=5Hz, 1H), 8.12 (brd, 1H), 8.22-8.30 (m, 2H), 8.69 (d, J=5Hz, 1H), 8.75 (s, 1H), 8.89 (s, 1H), 9.01-9.05 (m, 2H), 9.08 (s, 1H), 13.90 (brs, 1H), 14.61 (brs, 1H); ESIMS found C28H23FN8 m/z 491.1 (M+H).
    Figure imgb1137
     N-(3-Fluoro-5-(2-(5-(pyridm-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-7-yl)benzyl)-N-isopropylpropan-2-amine 17.
  • White solid (61 mg, 0.12 mmol, 65.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.93 (d, J=6Hz, 12H), 2.90-3.00 (m, 2H), 3.70 (s, 2H), 7.25 (d, J=9Hz, 1H), 7.58 (dd, J=8Hz, J=5Hz, 1H), 8.09 (s, 1H), 8.14 (brd, 1H), 8.24 (d, J=8Hz, 2H), 8.67 (dd, J=5Hz, J=2Hz, 1H), 8.70 (s, 1H), 8.88 (s, 1H), 9.03 (d, J=2Hz, 1H), 9.05 (d, J=2Hz, 1H), 9.07 (s, 1H), 13.88 (brs, 1H), 14.58 (brs, 1H); ESIMS found C30H29FN8 mlz 521.3 (M+H).
    Figure imgb1138
     3-(7-(3-Fluoro-5-(4-methylpiperidin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-6]pyridine 19.
  • Yellow solid (72 mg, 0.14 mmol, 100% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.79 (brd, 3H), 0.96-1.09 (m, 2H), 1.12-1.23 (m, 1H), 1.34-1.44 (m, 2H), 2.55-2.66 (m, 2H), 3.77 (brd, 2H), 6.81 (brd, 1H), 7.38-7.47 (m, 1H), 7.59 (dd, J=8Hz, J=5Hz, 1H), 7.90 (s, 1H), 8.22 (brd, 1H), 8.68 (d, J=4Hz, 1H), 8.72 (s, 1H), 8.88 (s, 1H), 9.00 (s, 1H), 9.02 (s, 2H), 13.92 (brs, 1H), 14.62 (s, 1H); ESIMS found C29H25FN8 m/z 505.1 (M+H).
    Figure imgb1139
     3-(7-(3-Fluoro-5-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 21.
  • Yellow solid (68 mg, 0.14 mmol, 86.5% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.69-2.77 (m, 4H), 3.13-3.21 (m, 4H), 6.82 (dd, J=10Hz, J=2Hz, 1H), 7.57 (dd, J=8Hz, J=5Hz, 1H), 7.56-7.67 (m, 2H), 8.20 (td, J=8Hz, J=2Hz, 1H), 8.66 (dd, J=5Hz, J=2Hz, 2H), 8.87 (s, 1H), 8.99 (d, J=2Hz, 1H), 9.02 (s, 2H); ESIMS found C27H22FN9 m/z 492.4 (M+H).
    Figure imgb1140
     3-(7-(5-Fluoropyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 23.
  • Off-white solid (69 mg, 0.17 mmol, 93.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.60 (dd, J=8Hz, J=5Hz, 1H), 8.27 (d, J=8Hz, 1H), 8.64-8.71 (m, 2H), 8.83-8.92 (m, 2H), 8.94 (s, 1H), 9.06 (d, J=2Hz, 1H), 9.08 (s, 1H), 9.10 (s, 1H), 9.44 (s, 1H), 14.00 (brs, 1H), 14.63 (brs, 1H); ESIMS found C22H13FN8 m/z 409.1 (M+H).
    Figure imgb1141
     5-(Pyridin-3-yl)-3-(7-(thiophen-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine 443.
  • Beige solid (3.4 mg, 0.009 mmol, 40.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.27 (t, J=4Hz, 1H), 7.65 (dd, J=5Hz, J=8Hz, 1H), 7.74 (d, J=5.5Hz, 1H), 8.22 (d, J=3.5Hz, 1H), 8.29 (d, J=8Hz, 1H), 8.70 (d, J=4.5Hz, 1H), 8.79 (s, 1H), 8.82 (s, 1H), 9.09 (d, J=1.5Hz, 2H), 9.26 (s, 1H), 13.87 (s, 1H), 14.60 (s, 1H); ESIMS found C21H13N7S m/z 396.1 (M+H).
    Figure imgb1142
     3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 590.
  • Brown solid (39.5 mg, 0.10 mmol, 30.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.31-7.40 (m, 4H), 7.45-7.52 (m, 1H), 7.54-7.63 (m, 2H), 8.09 (dt, J=1.5Hz, J=7Hz, 1H), 8.19 (d, J=8Hz, 1H), 8.67 (d, J=4Hz, 1H), 9.00 (d, J=2Hz, 1H), 9.03 (s, 2H), 13.36 (brs, 1H), 14.35 (brs, 1H); ESIMS found C24H15FN6 m/z 407.2 (M+H).
    Figure imgb1143
     5-(Pyridin-3-yl)-3-(4-(thiophen-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine 888.
  • Off-white solid (32.3 mg, 0.08 mmol, 25.3% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.23 (dd, J=3.5Hz, J=5Hz, 1H), 7.31 (t, J=7.5Hz, 1H), 7.48 (d, J=7.5Hz, 1H), 7.62-7.68 (m, 3H), 8.16 (d, J=3Hz, 1H), 8.29 (td, J=2Hz, J=8Hz, 1H), 8.70 (dd, J=1Hz, J=4.5Hz, 1H), 9.08 (d, J=2Hz, 1H), 9.10 (d, J=2Hz, 1H), 9.34 (d, J=2.5Hz, 1H), 13.41 (s, 1H), 14.39 (s, 1H); ESIMS found C22H14N6S m/z 395.1 (M+H).
    • Example 2.
  • Preparation of N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (2) is depicted below in Scheme 23.
    Figure imgb1144
    • Steps 1-2
  • A solution of 5-bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-carbaldehyde (XI) (436 mg, 1.4 mmol), bis(pinacolato)diboron (426 mg, 1.6 mmol), and KOAc (412 mg, 4.2 mmol) in dry DMF (20 ml) was purged with argon. PdCl2(dppf)2 (68 mg, 0.08 mmol) was added to the solution and purged again with argon. The solution was heated at 90°C for 2 h under argon and cooled to the room temperature. N-(5-bromopyridin-3-yl)pivalamide (XVII) (358 mg, 1.4 mmol), potassium phosphate (446 mg, 2.1 mmol) and water (2 mL) was added to the solution and purged with argon. Pd(PPh3)4 was then added and the solution was again purged with the argon. The solution was heated at 90°C for 4 h under argon. The solution was filtered through a bed of Celite and the solvent was distilled under vacuum. The crude product was suspended in water, sonicated briefly. The solids were filtered, dried under vacuum and purified by flash chromatography (100% DCM → 3:97 MeOH:DCM) to get N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-y1)pyridin-3-yl)pivalamide (LXV) as a brown solid (390 mg, 0.96 mmol, 68% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.27 (s, 9H), 1.58-1.69 (m, 2H), 1.78-1.90 (m, 1H), 2.02-2.14 (m, 2H), 2.49-2.57 (m, 1H), 3.78 (dt, J=11Hz, J=4Hz, 1H), 3.94-4.03 (d, J=11Hz, 1H), 6.25 (dd, J=10Hz, J=2Hz, 1H), 8.44 (t, J=2Hz, 1H), 8.72 (dd, J=4Hz, J=2Hz, 2H), 8.98 (d, J=2Hz, 1H), 9.09 (d, J=2Hz, 1H), 9.60 (s, 1H), 10.21 (s, 1H); ESIMS found C22H25N5O3 m/z 408 (M+H).
    • Steps 3-4
  • A solution of N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (LXV) (75 mg, 0.18 mmol), sulfur (64 mg, 0.20 mmol) and 5-(3-fluorophenyl)pyridine-3,4-diamine (XL) (41 mg, 0.20 mmol) in n-butanol (10 mL) was refluxed overnight under argon. The solution was cooled and filtered and dried under vacuum for 1 h. The residue was taken in dry DCM (5 mL). Triethylsilane (72 µL, 0.45 mmol) followed by TFA (2.5 mL) was added to the solution and stirred for 2 h at room temperature. The solvent was removed under vacuum. Water was added to the residue, sonicated briefly and basified with a 5N NH4OH solution. The solids formed were filtered, washed with cold water and dried at room temperature. The solids were boiled in DCM, cooled to room temperature and sonicated briefly. The solids were filtered, washed with DCM and dried under vacuum to give N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (2) as a brown solid (66 mg, 0.13 mmol, 72% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.30 (s, 9H), 7.22 (t, 1H), 7.57-7.66 (m, 1H), 8.25 (d, 1H), 8.36 (d, 1H), 8.55 (s, 1H), 8.74 (s, 1H), 8.78 (s, 1H), 8.89 (s, 1H), 8.97 (s, 1H), 9.04 (s, 1H), 9.07 (s, 1H), 9.61 (s, 1H), 13.92 (brs, 1H), 14.63 (brs, 1H); ESIMS found C28H23FN8O m/z 507.5 (M+H).
  • The following compounds were prepared in accordance with the procedure described in the above Example 2.
    Figure imgb1145
     2,2,2-Trifluoro-N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c] pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)acetamide 1.
  • Yellow solid (22 mg, 0.04 mmol, 92.3% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.20 (t, 1H), 7.60 (q, J=7Hz, 1H), 8.18 (d, 1H), 8.42 (d, 1H), 8.53 (s, 1H), 8.78 (s, 1H), 8.90 (s, 1H), 8.92 (s, 1H), 8.94 (s, 1H), 9.08 (s, 1H), 9.12 (s, 1H), 13.94 (brs, 1H), 14.64 (brs, 1H); ESIMS found C25H14F4N8O m/z 519.3 (M+H).
    Figure imgb1146
     3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 4.
  • Brown solid (72 mg, 0.14 mmol, 53% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.29 (s, 3H), 2.52-2.58 (m, 4H), 3.29-3.38 (m, 4H), 7.29 (t, 1H), 7.58 (q, J=7Hz, 1H), 7.68 (s, 1H), 8.17 (d, J=8Hz, 1H), 8.36 (d, J=11Hz, 1H), 8.41 (d, J=6Hz, 2H), 8.75 (s, 1H), 8.89 (s, 1H), 9.06 (s, 2H), 13.89 (brs, 1H), 14.59 (brs, 1H); ESIMS found C28H24FN9 m/z 506.4 (M+H).
    Figure imgb1147
     5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-amine 5.
  • Brown solid (68 mg, 0.16 mmol, 85% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 5.51 (s, 2H), 7.26-7.34 (m, 2H), 7.61 (q, J=8Hz, 1H), 8.03 (d, J=2Hz, 1H), 8.17 (d, J=2Hz, 1H), 8.21 (d, J=8Hz, 1H), 8.35 (d, J=11Hz, 1H), 8.68 (s, 1H), 8.89 (s, 1H), 8.93 (d, J=2Hz, 1H), 9.01 (s, 1H), 13.89 (s, 1H), 14.57 (s, 1H); ESIMS found C23H15FN8 m/z 423.1 (M+H).
    Figure imgb1148
     N1-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N2,N2-dimethylethane-1,2-diamine 6.
  • Brown solid (68 mg, 0.14 mmol, 53% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.26 (s, 6H), 2.53-2.61 (m, 2H), 3.22-3.31 (m, 2H), 5.91 (brs, 1H), 7.24-7.34 (m, 2H), 7.59 (q, J=8Hz, 1H), 8.11 (d, J=2Hz, 1H), 8.19 (d, J=2Hz, 2H), 8.37 (brd, 1H), 8.75 (s, 1H), 8.90 (s, 1H), 9.00 (s, 1H), 9.03 (s, 1H), 13.87 (brs, 1H), 14.56 (brs, 1H); ESIMS found C27H24FN9 m/z 494.4 (M+H).
    Figure imgb1149
     5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N,N-dimethylpyridin-3-amine 7.
  • Brown solid (68 mg, 0.15 mmol, 63% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.05 (s, 6H), 7.30 (t, J=7Hz, 1H), 7.41 (s, 1H), 7.57 (q, J=7Hz, 1H), 8.15 (d, J=8Hz, 1H), 8.21 (d, J=2.5Hz, 1H), 8.30 (s, 1H), 8.35 (d, J=11Hz, 1H), 8.74 (s, 1H), 8.89 (s, 1H), 9.05 (s, 2H), 13.89 (s, 1H), 14.58 (s, 1H); ESIMS found C25H19FN8 m/z 451.1 (M+H).
    Figure imgb1150
     5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-isopropylpyridin-3-amine 9.
  • Brown solid (79 mg, 0.17 mmol, 68% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.18 (d, J=6Hz, 6H), 3.71 (sep, J=7Hz, 1H), 5.91 (d, J=8Hz, 1H), 7.21 (s, 1H), 7.28 (t, J=8Hz, 1H), 7.58 (q, J=8Hz, 1H), 8.04 (d, J=2.5Hz, 1H), 8.14 (d, J=2Hz, 1H), 8.17 (d, J=8Hz, 1H), 8.32 (d, J=10Hz, 1H), 8.74 (s, 1H), 8.89 (s, 1H), 8.97 (s, 1H), 9.00 (s, 1H), 13.89 (s, 1H), 14.57 (s, 1H); ESIMS found C26H21FN8 m/z 465.3 (M+H).
    Figure imgb1151
     1-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-6]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamme 18.
  • Off-white solid (39 mg, 0.08 mmol, 76.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.25 (s, 6H), 3.58 (s, 2H), 7.31 (t, J=8Hz, 1H), 7.61 (q, J=7Hz, 1H), 8.12 (s, 1H), 8.20 (d, J=8Hz, 1H), 8.37 (d, J=10Hz, 1H), 8.60 (s, 1H), 8.76 (s, 1H), 8.89 (s, 1H), 8.98 (s, 1H), 9.10 (s, 2H), 13.91 (s, 1H), 14.61 (s, 1H); ESIMS found C26H21FN8 m/z 465.3 (M+H).
    Figure imgb1152
     1-(5-(3-(7-(5-Fluoropyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 20.
  • Off-white solid (14 mg, 0.03 mmol, 21.5% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.22 (s, 6H), 3.58 (s, 2H), 8.11 (s, 1H), 8.59 (s, 1H), 8.67 (s, 1H), 8.77-8.90 (m, 2H), 8.95 (s, 2H), 9.07 (s, 2H), 9.43 (brs, 1H), 13.99 (brs, 1H), 14.63 (brs, 1H); ESIMS found C25H20FN9 m/z 466 (M+H).
    Figure imgb1153
     N-(3-(2-(5-(5-((Dimethylammo)methyl)pyridin-3-yl)-1H-pyrazolo [3,4-b]pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-7-yl)-5-fluorobenzyl)methanesulfonamide 22.
  • Off-white solid (49 mg, 0.09 mmol, 62.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.23 (brs, 6H), 2.90 (s, 3H), 3.58 (brs, 2H), 4.32 (d, J=6Hz, 2H), 7.28 (d, J=9Hz, 1H), 7.73 (t, J= 8Hz, 1H), 8.08 (s, 1H), 8.35 (d, J=10Hz, 1H), 8.60 (s, 1H), 8.75 (s, 1H), 8.90 (s, 1H), 8.97 (s, 1H), 9.07 (s, 1H), 9.09 (s, 1H), 13.92 (s, 1H), 14.61 (s, 1H); ESIMS found C28H26FN9O2S m/z 572.0 (M+H).
    Figure imgb1154
     1-(5-(3-(7-(3-Fluoro-5-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylinethanamine 24.
  • Off-white solid (52 mg, 0.09 mmol, 72.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.22 (s, 6H), 3.14-3.21 (m, 4H), 3.47-3.56 (m, 4H), 3.57 (s, 2H), 6.85 (d, J=12Hz, 1H), 7.62 (d, J=10Hz, 1H), 7.74 (s, 1H), 8.07 (s, 1H), 8.59 (s, 1H), 8.72 (s, 1H), 8.87 (s, 1H), 8.90 (s, 1H), 9.02 (s, 1H), 9.03 (s, 1H), 13.86 (brs, 1H), 14.60 (brs, 1H); ESIMS found C30H28FN9O m/z 550.5 (M+H).
    Figure imgb1155
     N,N-Dimethyl-1-(5-(3-(7-(5-(trifluoromethyl)pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 25.
  • Off-white solid (51 mg, 0.10 mmol, 91.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.20 (s, 6H), 3.56 (s, 2H), 8.03 (s, 1H), 8.60 (d, J=1.5Hz, 1H), 8.87 (s, 1H), 8.91-9.00 (m, 3H), 9.02 (d, J=2Hz, 1H), 9.03 (s, 1H), 9.36 (s, 1H), 9.73 (s, 1H), 14.01 (brs, 1H), 14.65 (brs, 1H); ESIMS found C26H20F3N9 m/z 516.3 (M+H).
    Figure imgb1156
     3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 27.
  • Beige solid (13.5 mg, 0.028 mmol, 15.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.75 (brs, 4H), 2.62 (brs, 4H), 3.84 (brs, 2H), 7.39 (t, J=9Hz, 2H), 8.17 (s, 1H), 8.41 (brs, 2H), 8.62 (d, J=1.5Hz, IN), 8.65 (brs, 1H), 8.86 (brs, 1H), 8.98 (s, 1H), 9.09(s, 2H), 13.84 (brs, 1H), 14.57 (brs, 1H); ESIMS found C28H23FN8 m/z 491.2 (M+H).
    Figure imgb1157
     3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 28.
  • Yellow solid (23 mg, 0.046 mmol, 35.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.40 (brs, 2H), 1.50 (brs, 4H), 2.40 (brs, 4H), 3.60 (s, 2H), 7.28 (t, J=7Hz, 1H), 7.60 (q, J=7Hz, 1H), 8.09 (s, 1H), 8.17 (brs, 1H), 8.39 (brd, J=9Hz, 1H), 8.58 (s, 1H), 8.75 (brs, 1H), 8.89 (s, 1H), 8.95 (s, 1H), 9.08 (s, 1H), 9.09 (s, 1H), 13.90 (brs, 1H), 14.58 (brs, 1H); ESIMS found C29H25FN8 m/z 505.5 (M+H).
    Figure imgb1158
     N-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopropanecarboxamide 114.
  • Off-white solid (6.8 mg, 0.014 mmol, 12.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.81-0.92 (m, 4H), 1.82-1.91 (m, 1H), 7.27 (brs, 1H), 7.61 (ABq, J=8Hz, 1H), 8.25 (brs, 1H), 8.30 (brs, 1H), 8.55 (brs, 1H), 8.72 (d, J=2Hz, 1H), 8.77 (brs, 2H), 8.91 (brs, 1H), 9.01 (d, J=2Hz, 1H), 9.06 (s, 1H), 10.62 (s, 1H), 13.96 (brs, 1H), 14.61 (s, 1H); ESIMS found C27H19FN8O m/z 491.2 (M+H).
    Figure imgb1159
     N-(5-(3-(7-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-2-phenylacetamide 128.
  • Brown solid (42.6 mg, 0.08 mmol, 42.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.78 (s, 2H), 7.26 (t, J=7Hz, 1H), 7.34 (t, J=8Hz, 2H), 7.39 (d, J=7Hz, 2H), 7.45 (t, J=8.5Hz, 2H), 8.32 (brs, 2H), 8.60 (s, 1H), 8.74 (brs, 1H), 8.75 (d, J=1.5Hz, 1H), 8.78 (s, 1H), 9.00 (d, J=2Hz, 1H), 9.04 (d, J=2Hz, 1H), 9.08 (brs, 1H), 10.67 (s, 1H), 14.76 (s, 1H); ESIMS found C31H21FN8O m/z 541.4 (M+H).
    Figure imgb1160
     1-Cyclopentyl-N-((5-(3-(7-(4-fluorophenyl)-3H-imidazo[4,5-c] pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methyl)methanamine 142.
  • Tan solid (6.4 mg, 0.012 mmol, 7.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.13-1.26 (m, 2H), 1.39-1.55 (m, 4H), 1.58-1.76 (m, 2H), 2.56 (d, J=5.5Hz, 2H), 2.03 (quin, J=7.5Hz, 1H), 3.93 (brs, 2H), 7.40 (t, J=9Hz, 2H), 8.24 (s, 1H), 8.43 (brs, 2H), 8.64 (s, 2H), 8.88 (brs, 1H), 8.96 (s, 1H), 9.08 (s, 1H), 9.11 (s, 1H); ESIMS found C30H27FN8 m/z 519.1 (M+H).
    Figure imgb1161
    Figure imgb1162
     N-(5-(3-(7-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)butyramide 158.
  • Brown solid (36.4 mg, 0.074 mmol, 40.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.92-1.02 (m, 3H), 1.69 (brs, 2H), 2.35-2.44 (m, 2H), 7.33-7.45 (m, 2H), 7.45-7.59 (m, 1H), 8.52 (s, 1H), 8.73 (d, J=13Hz, 1H), 8.91 (t, J=6.5Hz, 2H), 8.99 (s, 2H), 10.31 (s, 1H), 13.84 (s, 1H), 14.48-14.63 (m, 1H); ESIMS found C27H21FN8O m/z 493.4 (M+H).
    Figure imgb1163
     N,N-Dimethyl-1-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 176.
  • Dark brown solid (24.5 mg, 0.055 mmol, 28.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.26 (s, 6H), 3.60 (s, 2H), 7.59 (dd, J=5.5Hz, J=8Hz, 1H), 8.11 (s, 1H), 8.58 (d, J=1.5Hz, 1H), 8.66 (d, J=3.5Hz, 1H), 8.73 (brs, 2H), 8.91 (brs, 1H), 8.96 (d, J=2Hz, 1H), 9.06 (brs, 2H), 9.49 (brs, 1H), 13.91 (brs, 1H), 14.58 (brs, 1H); ESIMS found C25H21N9 m/z 448.1 (M+H).
    Figure imgb1164
     5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine 178.
  • Brown solid (1.2 mg, 0.002 mmol, 0.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.36-1.79 (m, 6H), 2.42-251 (m, 4H), 3.62 (s, 2H), 7.60 (dd, J=7.5Hz, J=4.5Hz, 2H), 8.66 (d, J=4.5Hz, 1H), 8.70 (s, 1H), 8.72 (s, 1H), 8.75 (s, 1H), 8.93 (s, 1H), 9.09 (brs, 3H), 9.58 (brs, 1H), 13.94 (s, 1H), 14.64 (brs, 1H); ESIMS found C28H25N9 mlz 488.3 (M+H).
    Figure imgb1165
     3,3-Dimethyl-N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)butanamide 179.
  • Brown solid (4.1 mg, 0.008 mmol, 4.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.07 (s, 9H), 2.30 (s, 2H), 7.65 (dd, J=5Hz, J=8Hz, 1H), 8.52 (s, 1H), 8.66 (d, J=3.5Hz, 1H), 8.70 (d, J=2Hz, 1H), 8.77 (brs, 1H), 8.81 (s, 2H), 8.99 (d, J=2Hz, 1H), 9.01 (d, J=2Hz, 1H), 9.05 (brs, 1H), 9.39 (brs, 1H), 10.27 (s, 1H), 14.71 (s, 1H); ESIMS found C28H25N9O m/z 504.3 (M+H).
    Figure imgb1166
     N-(5-(3-(7-(Pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)cyclohexanecarboxamide 185.
  • Brown solid (16.2 mg, 0.03 mmol, 18.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.20-1.38 (m, 3H), 1.47 (dq, J=2.5Hz, J=12Hz, 2H), 1.69 (d, J=12.5Hz, 1H), 1.81 (d, J=12.5Hz, 2H), 1.90 (d, J=10.5Hz, 2H), 2.43 (tt, J=3.5Hz, J=11.5Hz, 1H), 7.64 (dd, J=4.5Hz, J=8Hz, 1H), 8.56 (brs, 1H), 8.63 (brs, 1H), 8.70 (d, J=2Hz, 1H), 8.80 (brs, 3H), 8.96 (brs, 1H), 9.00 (s, 2H), 9.41 (brs, 1H), 10.26 (s, 1H), 13.98 (brs, 1H), 14.63 (s, 1H); ESIMS found C29H25N9O m/z 516.3 (M+H).
    Figure imgb1167
     5-(4-Methylpyridin-3-yl)-3-(7-(pyridin-4-yl)-3H-imidazo[4,5-c] pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine 192.
  • Beige solid (25.6 mg, 0.06 mmol, 71.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.42 (s, 3H), 7.49 (d, J=5Hz, 1H), 8.34 (brs, 2H), 8.55 (d, J=5Hz, 1H), 8.60 (s, 1H), 8.69 (d, J=4.5Hz, 2H), 8.78 (s, 2H), 8.87 (s, 1H), 8.97 (s, 1H), 13.99 (brs, 1H), 14.63 (s, 1H), ; ESIMS found C23H16N8 m/z 405.2 (M+H).
    Figure imgb1168
     N-Isopropyl-5-(3-(7-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-6]pyridin-5-yl)pyridin-3-amine 198.
  • Tan solid (1.3 mg, 0.003 mmol, 1.5% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.04 (d, J=6.5Hz, 6H), 3.76 (sep, J=6.5Hz, 1H), 6.06 (brs, 1H), 7.34 (s, 1H), 8.06 (d, J=2Hz, 1H), 8.21 b(s, 1H), 8.40 (brs, 2H), 8.69 (d, J=6Hz, 2H), 8.83 (brs, 1H), 8.97 (brs, 1H), 9.00 (s, 1H), 9.04 (s, 1H), 14.03 (brs, 1H), 14.60 (s, 1H); ESIMS found C25H21N9 m/z 448.0 (M+H).
    Figure imgb1169
     N-Benzyl-1-(5-(3-(7-(pyridm-4-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 209.
  • Beige solid (17.2 mg, 0.034 mmol, 33.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 4.01 (s, 2H), 4.09 (s, 2H), 7.30 (t, J=7Hz, 1H), 7.37 (t, J=8Hz, 2H), 7.45 (d, J=7.5Hz, 2H), 8.31 (s, 1H), 8.33 (d, J=5Hz, 2H), 8.67 (s, 1H), 8.68 (dd, J=1.5Hz, J=5Hz, 1H), 8.73 (dd, J=1.5Hz, J=4.5Hz, 2H), 8.76 (d, J=6Hz, 2H), 9.15 (s, 2H), 14.65 (brs, 1H); ESIMS found C30H23N9 m/z 510.2 (M+H).
    Figure imgb1170
     N-(5-(3-(7-(Pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)cyclobutanecarboxamide 229.
  • Tan solid (8.5 mg, 0.017 mmol, 5.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.82-1.93 (m, 1H), 1.95-2.06 (m, 1H), 2.15-2.25 (m, 2H), 2.26-2.34 (m, 2H), 7.40-7.47 (m, 2H), 7.95 (dt, J=2Hz, J=8Hz, 1H), 8.15 (d, J=8Hz, 1H), 8.42 (s, 1H), 8.75 (s, 1H), 8.77 (d, J=1Hz, 1H), 8.78 (s, 1H), 8.89 (s, 1H), 9.06 (s, 2H), 10.20 (s, 1H), 13.05 (brs, 1H), 14.65 (s, 1H); ESIMS found C27H21N9O m/z 488.2 (M+H).
    Figure imgb1171
     5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-amine 238.
  • Tan solid (7.5 mg, 0.018 mmol, 8.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.61 (brs, 6H), 3.49 (brs, 4H), 5.65 (brs, 2H), 6.69 (s, 1H), 7.36 (s, 1H), 8.02 (s, 1H), 8.19 (s, 1H), 8.65 (s, 1H), 8.89 (s, 1H), 8.92 (d, J=2Hz, 1H), 13.04 (s, 1H), 14.36 (s, 1H); ESIMS found C22H21N9 m/z 412.3 (M+H).
    Figure imgb1172
     N-((5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methyl)ethanamine 241.
  • Brown solid (9.9 mg, 0.022 mmol, 11.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.08 (t, J=7Hz, 3H), 1.60 (brs, 6H), 2.61 (q, J=7Hz, 2H), 3.48 (brs, 4H), 3.85 (s, 2H), 6.67 (brs, 1H), 8.19 (s, 1H), 8.60 (d, J=1.5Hz, 1H), 8.64 (brs, 1H), 8.89 (d, J=2.5Hz, 1H), 8.97 (d, J=2Hz, 1H), 9.00 (d, J=2.5Hz, 1H), 12.95 (brs, 1H); ESIMS found C25H27N9 m/z 454.2 (M+H).
    Figure imgb1173
     N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)benzamide 246.
  • Brown solid (33.1 mg, 0.064 mmol, 37.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.60 (brs, 6H), 3.49 (brs, 4H), 6.67 (s, 1H), 7.59 (t, J=7Hz, 2H), 7.65 (t, J=7Hz, 1H), 8.05 (d, J=8Hz, 2H), 8.58 (t, J=2Hz, 1H), 8.65 (s, 1H), 8.79 (d, J=2Hz, 1H), 8.97 (d, J=2Hz, 1H), 9.02 (d, J=2Hz, 1H), 9.14 (d, J=2Hz, 1H), 10.65 (s, 1H), 13.01 (s, 1H), 14.40 (s, 1H); ESIMS found C29H25N9O m/z 516.4 (M+H).
    Figure imgb1174
     3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 249.
  • Beige solid (26.5 mg, 0.055 mmol, 30.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.61 (brs, 6H), 1.74 (brs, 4H), 2.54 (brs, 4H), 3.49 (brs, 4H), 3.76 (brs, 2H), 6.67 (s, 1H), 8.13 (s, 1H), 8.59 (d, J=1.5Hz, 1H), 8.65 (s, 1H), 8.91 (d, J=2Hz, 1H), 8.95 (d, J=2Hz, 1H), 9.00 (d, J=2.5Hz, 1H), 12.99 (s, 1H), 14.37 (brs, 1H); ESIMS found C27H29N9 m/z 480.1 (M+H).
    Figure imgb1175
     N-(5-(3-(7-(Piperidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopropanecarboxamide 254.
  • Yellow-white solid (8.6 mg, 0.018 mmol, 8.2% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.82-0.92 (m, 4H), 1.61 (brs, 6H), 1.81-1.88 (m, 1H), 3.49 (brs, 4H), 6.67 (s, 1H), 8.40 (s, 1H), 8.65 (s, 1H), 8.71 (d, J=2Hz, 1H), 8.88 (d, J=2Hz, 1H), 8.91 (d, J=1.5Hz, 1H), 8.97 (d, J=2Hz, 1H), 10.63 (s, 1H), 13.00 (s, 1H), 14.38 (s, 1H); ESIMS found C26H25N9O m/z 480.1 (M+H).
    Figure imgb1176
     N-(5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pentanamide 305.
  • Brown solid (30.4 mg, 0.06 mmol, 33.7% yield). 1H NMR (CD3OD, 500 MHz) δ ppm 1.00 (t, J=7.5Hz, 3H), 1.46 (sex, J=7.5Hz, 2H), 1.74 (quin, J=7.5Hz, 2H), 2.48 (t, J=7.5Hz, 2H), 2.79 (s, 3H), 3.19 (brs, 4H), 3.72 (brs, 4H), 6.94 (brs, 1H), 8.54 (s, 1H), 8.65 (brs, 1H), 8.70 (d, J=2Hz, 1H), 8.79 (d, J=2Hz, 1H), 8.91 (d, J=2Hz, 1H), 9.10 (d, J=1.5Hz, 1H); ESIMS found C27H30N10O m/z 511.5 (M+H).
    Figure imgb1177
     N-(5-(3-(7-(4-Methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclohexanecarboxamide 309.
  • Brown solid (25.9 mg, 0.05 mmol, 28.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.15-1.36 (m, 3H), 1.45 (dq, J=3Hz, J=12Hz, 2H), 1.67 (d, J=12.5Hz, 1H), 1.78 (d, J=12Hz, 2H), 1.87 (d, J=12.5Hz, 2H), 2.34-2.45 (m, 4H), 2.66 (brs, 4H), 3.52 (brs, 4H), 6.73 (s, 1H), 8.42 (t, J=2Hz, 1H), 8.68 (s, 1H), 8.70 (d, J=2Hz, 1H), 8.89 (d, J=2.5Hz, 1H), 8.91 (d, J=2Hz, 1H), 8.97 (d, J=2Hz, 1H), 10.24 (s, 1H), 13.13 (s, 1H), 14.42 (s, 1H); ESIMS found C29H32N10O m/z 537.4 (M+H).
    Figure imgb1178
     5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-isopropylpyridin-3-amine 325.
  • Tan solid (11.8 mg, 0.032 mmol, 16.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.20 (d, J=6Hz, 6H), 3.75 (sep, J=6.5Hz, 1H), 5.91 (d, J=8Hz, 1H), 7.27 (t, J=2.5Hz, 1H), 8.03 (d, J=2.5Hz, 1H), 8.14 (d, J=1.5Hz, 1H), 8.35 (d, J=5.5Hz, 1H), 8.93 (d, J=2Hz, 1H), 8.95 (d, J=2.5Hz, 1H), 9.01 (brs, 1H), 13.63 (brs, 1H); ESIMS found C20H18N8 m/z 370.9 (M+H).
    Figure imgb1179
     1-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N-benzylmethanamine 336.
  • Beige solid (12.0 mg, 0.028 mmol, 27.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.77 (s, 2H), 3.85 (s, 2H), 7.23 (t, J=7.5Hz, 1H), 7.33 (t, J=8Hz, 2H), 7.40 (d, J=7Hz, 2H), 7.61 (s, 1H), 8.21 (s, 1H), 8.35 (d, J=5.5Hz, 1H), 8.61 (d, J=2Hz, 1H), 8.90 (d, J=2.5Hz, 1H), 9.02 (dd, J=2Hz, J=6.5Hz, 3H), 13.60 (brs, 1H); ESIMS found C25H20N8 m/z 433.1 (M+H).
    Figure imgb1180
     N,N-Dimethyl-5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-amine 346.
  • Tan solid (5.8 mg, 0.013 mmol, 6.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.14 (s, 6H), 7.74 (s, 1H), 7.78 (dd, J=3Hz, J=5Hz, 1H), 8.15 (d, J=4.5Hz, 1H), 8.25 (d, J=3Hz, 1H), 8.46 (d, J=1.5Hz, 1H), 8.92 (s, 2H), 9.02 (s, 1H), 9.13 (d, J=2Hz, 1H), 9.14 (d, J=2.5Hz, 1H), 14.83 (s, 1H); ESIMS found C23H18N8S m/z 439.1 (M+H).
    Figure imgb1181
    Figure imgb1182
     N,N-Dimethyl-1-(5-(3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 352.
  • Dark brown solid (24.4 mg, 0.054 mmol, 28.2% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.28 (s, 6H), 3.62 (brs, 2H), 7.74 (dd, J=3Hz, J=5Hz, 1H), 8.12-8.18 (m, 2H), 8.59 (s, 1H), 8.78 (brs, 1H), 8.81 (s, 2H), 9.00 (s, 1H), 9.09 (s, 1H), 9.13 (s, 1H), 13.80 (brs, 1H), 14.59 (brs, 1H); ESIMS found C24H20N8S m/z 453.0 (M+H).
    Figure imgb1183
     5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-3-(7-(thiophen-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine 354.
  • Brown solid (17.8 mg, 0.04 mmol, 52.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.40 (brs, 2H), 1.52 (brs, 4H), 2.43 (brs, 4H), 3.63 (s, 2H), 7.74 (dd, J=3Hz, J=4.5Hz, 1H), 8.11-8.18 (m, 2H), 8.60 (s, 1H), 8.78 (s, 1H), 8.81 (s, 2H), 8.98 (s, 1H), 9.08 (s, 1H), 9.14 (s, 1H), 13.81 (brs, 1H), 14.59 (brs, 1H); ESIMS found C27H24N8S m/z 493.3 (M+H).
    Figure imgb1184
     N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide 373.
  • Tan solid (21.6 mg, 0.045 mmol, 25.5% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.30 (s, 9H), 7.43 (brs, 1H), 7.85 (s, 1H), 8.59 (brs, 1H), 8.71 (s, 1H), 8.78 (d, J=1.5Hz, 1H), 8.83 (brs, 2H), 8.95 (d, J=2Hz, 1H), 9.04 (d, J=2.5Hz, 1H), 9.09 (s, 1H), 9.63 (s, 1H), 13.86 (brs, 1H), 14.61 (s, 1H); ESIMS found C26H22N8O2 m/z 479.0 (M+H).
    Figure imgb1185
     N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)benzamide 376.
  • Brown solid (49.9 mg, 0.10 mmol, 58.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.47 (brs, 1H), 7.60 (t, J=7.5Hz, 2H), 7.66 (t, J=7Hz, 1H), 7.86 (t, J=2Hz, 1H), 8.06 (d, J=8Hz, 2H), 8.76 (s, 1H), 8.78 (s, 1H), 8.85 (d, J=2Hz, 1H), 8.90 (brs, 1H), 8.93 (brs, 1H), 9.05 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 9.13 (d, J=2Hz, 1H), 10.68 (s, 1H), 14.74 (s, 1H); ESIMS found C28H18N8O2 m/z 499.3 (M+H).
    Figure imgb1186
     N-(5-(3-(7-(Furan-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)butyramide 382.
  • Brown solid (32.2 mg, 0.069 mmol, 38.3% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.96 (t, J=7Hz, 3H), 1.67 (sex, J=7Hz, 2H), 2.39 (t, J=7.5Hz, 2H), 7.44 (s, 1H), 7.86 (t, J=1.5Hz, 1H), 8.58 (s, 1H), 8.72 (s, 1H), 8.75 (d, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 8.81 (s, 1H), 8.83 (s, 1H), 9.01 (d, J=2.5Hz, 1H), 9.07 (d, J=2Hz, 1H), 10.32 (s, 1H), 13.92 (brs, 1H), 14.62 (s, 1H); ESIMS found C25H20N8O2 m/z 465.0 (M+H).
    Figure imgb1187
     N-(5-(3-(7-(Thiophen-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide 440.
  • Dark brown solid (33.7 mg, 0.07 mmol, 38.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.17 (t, J=7.5Hz, 3H), 2.48 (q, J=7.5Hz, 2H), 7.29 (dd, J=4Hz, J=5Hz, 1H), 7.69-7.76 (m, 2H), 8.21 (brs, 1H), 8.73 (s, 2H), 8.76 (s, 1H), 8.82 (s, 1H), 8.84 (s, 1H), 9.07 (d, J=2Hz, 1H), 9.21 (s, 1H), 10.37 (s, 1H), 14.65 (s, 1H); ESIMS found C24H18N8OS m/z 466.9 (M+H).
    Figure imgb1188
     N,N-Dimethyl-1-(5-(3-(7-(thiophen-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 452.
  • Beige solid (100.3 mg, 0.22 mmol, 29.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.24 (s, 6H), 3.58 (s, 2H), 7.27 (dd, J=3.5Hz, J=5Hz, 1H), 7.69 (d, J=5Hz, 1H), 8.15 (s, 1H), 8.22 (brs, 1H), 8.59 (s, 1H), 8.79 (s, 1H), 8.81 (s, 1H), 9.00 (d, J=2Hz, 1H), 9.10 (d, J=2Hz, 1H), 9.24 (s, 1H), 13.87 (brs, 1H), 14.59 (brs, 1H); ESIMS found C24H20N8S m/z 453.1 (M+H).
    Figure imgb1189
     N-(5-(3-(7-(Thiophen-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopropanecarboxamide 458.
  • Dark yellow solid (15 mg, 0.03 mmol, 36.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.90 (d, J=6Hz, 4H), 1.90 (quin, J=6Hz, 1H), 7.27 (t, J=5Hz, 1H), 7.66 (d, J=5Hz, 1H), 8.22 (d, J=3Hz, 1H), 8.67 (s, 1H), 8.73 (s, 1H), 8.76 (s, 1H), 8.79 (s, 1H), 8.82 (s, 1H), 9.06 (s, 1H), 9.21 (s, 1H), 10.67 (s, 1H), 13.88 (brs, 1H), 14.61 (s, 1H); ESIMS found C25H18N8OS m/z 479.1 (M+H).
    Figure imgb1190
     1-Cyclopentyl-N-((5-(3-(7-(thiophen-2-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methyl)methanamine 463.
  • Tan solid (15.0 mg, 0.03 mmol, 17.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.12-1.21 (m, 2H), 1.40-1.55 (m, 4H), 1.65-1.74 (m, 2H), 2.01 (quin, J=7.5Hz, 1H), 2.52 (d, J=5.5Hz, 2H), 3.90 (s, 2H), 2.27 (dd, J=3.5Hz, J=5Hz, 1H), 7.71 (d, J=5Hz, 1H), 8.22 (brs, 1H), 8.25 (s, 1H), 8.64 (d, J=1.5Hz, 1H), 8.79 (s, 1H), 8.80 (s, 1H), 8.97 (d, J=2Hz, 1H), 9.10 (d, J=2Hz, 1H), 9.27 (d, J=1.5Hz, 1H); ESIMS found C28H26N8S m/z 507.1 (M+H).
    Figure imgb1191
     N-((5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)methyl)ethanamine 547.
  • Tan solid (9.4 mg, 0.02 mmol, 10.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.06 (t, J=7.5Hz, 3H), 2.60 (q, J=7.5Hz, 2H), 3.85 (s, 2H), 7.23 (dt, J=2.5Hz, J=8.5Hz, 1H), 7.38 (t, J=8Hz, 1H), 7.53-7.65 (m, 3H), 8.14 (d, J=8Hz, 1H), 8.17 (s, 1H), 8.39 (d, J=11Hz, 1H), 8.62 (d, J=1.5Hz, 1H), 8.92 (d, J=2Hz, 1H), 9.06 (d, J=2Hz, 1H), 9.13 (s, 1H), 13.43 (brs, 1H); ESIMS found C27H22FN7 m/z 464.0 (M+H).
    Figure imgb1192
     5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)-N-isopropylpyridin-3-amine 551.
  • Dark yellow solid (15.6 mg, 0.03 mmol, 17.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.19 (d, J=6.5Hz, 6H), 3.72 (sep, J=6.5Hz, 1H), 5.87 (d, J=8Hz, 1H), 7.21 (dd, J=5Hz, J=2.5Hz, 2H), 7.37 (t, J=7.5Hz, 1H), 7.54 (q, J=8Hz, 1H), 7.55-7.61 (m, 2H), 8.04 (d, J=2.5Hz, 1H), 8.12 (d, J=8Hz, 1H), 8.14 (d, J=2Hz, 1H), 8.32 (dd, J=2Hz, J=8Hz, 1H), 8.95 (d, J=2.5Hz, 1H), 9.02 (d, J=2.5Hz, 1H), 13.41 (s, 1H), 14.35 (s, 1H); ESIMS found C27H22FN7 m/z 464.2 (M+H).
    Figure imgb1193
     1-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine 552.
  • Brown solid (23.6 mg, 0.051 mmol, 26.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.22 (s, 6H), 3.56 (s, 2H), 7.24 (dt, J=2.5Hz, J=8.5Hz, 1H), 7.37 (t, J=8Hz, 1H), 7.53-7.61 (m, 3H), 8.09 (s, 1H), 8.13 (d, J=8Hz, 1H), 8.36 (dd, J=2Hz, J=11.5Hz, 1H), 8.58 (d, J=1.5Hz, 1H), 8.96 (d, J=2.5Hz, 1H), 9.06 (d, J=2Hz, 1H), 9.11 (d, J=2.5Hz, 1H), 13.43 (brs, 1H), 14.39 (brs, 1H); ESIMS found C27H22FN7 m/z 464.3 (M+H).
    Figure imgb1194
     3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 554.
  • Light brown solid (57.4 mg, 0.11 mmol, 43.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.39 (brs, 2H), 1.50 (brs, 4H), 2.40 (brs, 4H), 3.60 (s, 2H), 7.22 (dt, J=3Hz, J=8.5Hz, 1H), 3.78 (t, J=8Hz, 1H), 7.51-7.62 (m, 3H), 8.09 (s, 1H), 8.11 (d, J=7.5Hz, 1H), 8.40 (d, J=11Hz, 1H), 8.59 (s, 1H), 8.95 (s, 1H), 9.06 (d, J=2.5Hz, 1H), 9.11 (d, J=2Hz, 1H), 13.44 (s, 1H), 14.40 (s, 1H); ESIMS found C30H26FN7 m/z 504.1 (M+H).
    Figure imgb1195
     N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)pentanamide 557.
  • Brown solid (36.9 mg, 0.073 mmol, 41.3% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.93 (t, J=7.5Hz, 3H), 1.38 (sex, J=7.5Hz, 2H), 1.64 (quin, J=7.5Hz, 2H), 2.42 (t, J=7.5Hz, 2H), 7.17 (dt, J=2Hz, J=8Hz, 1H), 7.38 (t, J=7.5Hz, 1H), 7.51-7.63 (m, 3H), 8.16 (brs, 1H), 8.31 (brs, 1H), 8.52 (s, 1H), 8.72 (d, J=2Hz, 1H), 8.81 (d, J=1.5Hz, 1H), 8.98 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.30 (s, 1H), 13.44 (brs, 1H), 14.41 (s, 1H); ESIMS found C29H24FN7O m/z 506.3 (M+H).
    Figure imgb1196
     N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopentanecarboxamide 560.
  • Brown solid (14.8 mg, 0.029 mmol, 16.5% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.55-1.64 (m, 2H), 1.64-1.73 (m, 2H), 1.73-1.83 (m, 2H), 1.86-1.96 (m, 2H), 2.88 (quin, J=8Hz, 1H), 7.16 (dt, J=2.5Hz, J=8.5Hz, 1H), 7.38 (t, J=8Hz, 1H), 7.51-7.61 (m, 3H), 8.19 (d, J=8Hz, 1H), 8.32 (dd, J=2Hz, J=10Hz, 1H), 8.55 (t, J=2Hz, 1H), 8.71 (d, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 8.98 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.27 (s, 1H), 13.44 (s, 1H), 14.41 (s, 1H); ESIMS found C30H24FN7O m/z 518.0 (M+H).
    Figure imgb1197
     N-(5-(3-(4-(3-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)cyclohexanecarboxamide 561.
  • Brown solid (14.0 mg, 0.026 mmol, 15.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.15-1.36 (m, 3H), 1.46 (dq, J=3Hz, J=12.5Hz, 2H), 1.68 (d, J=12.5Hz, 1H), 1.80 (dd, J=2.5Hz, J=11.5Hz, 2H), 1.90 (d, J=12.5Hz, 2H), 2.42 (tt, J=3.5Hz, J=11.5Hz, 1H), 7.15 (t, J=7.5Hz, 1H), 7.38 (t, J=7.5Hz, 1H), 7.53-7.65 (m, 3H), 8.19 (d, J=7Hz, 1H), 8.32 (d, J=10.5Hz, 1H), 8.54 (s, 1H), 8.70 (d, J=2Hz, 1H), 8.82 (d, J=1.5Hz, 1H), 8.98 (d, J=2Hz, 1H), 9.07 (s, 1H), 10.22 (s, 1H), 13.44 (s, 1H), 14.41 (s, 1H); ESIMS found C31H26FN7O m/z 532.2 (M+H).
    Figure imgb1198
     N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)benzamide 573.
  • Tan solid (37.9 mg, 0.072 mmol, 42.2% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.32-7.41 (m, 3H), 7.50 (brd, J=6.5Hz, 1H), 7.55 (brd, J=7.5Hz, 1H), 7.60 (t, J=7.5Hz, 2H), 7.66 (t, J=7.5Hz, 1H), 8.07 (d, J=7.5Hz, 2H), 8.40 (brs, 2H), 8.79 (brs, 1H), 8.82 (d, J=2Hz, 1H), 9.01 (s, 1H), 9.05 (d, J=2Hz, 1H), 9.11 (s, 1H), 10.71 (s, 1H), 13.39 (brs, 1H), 14.41 (s, 1H); ESIMS found C31H20FN7O m/z 526.1 (M+H).
    Figure imgb1199
     N-(5-(3-(4-(4-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopropanecarboxamide 581.
  • Brown solid (34.5 mg, 0.07 mmol, 40.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.85-0.96 (m, 4H), 1.85-1.93 (m, 1H), 7.26-7.29 (m, 3H), 7.50 (d, J=7Hz, 1H), 7.55 (d, J=7Hz, 1H), 8.39 (brs, 2H), 8.66 (s, 1H), 8.73 (d, J=2Hz, 1H), 9.01 (d, J=2Hz, 1H), 9.05 (d, J=1.5Hz, 1H), 10.69 (s, 1H), 13.38 (brs, 1H), 14.40 (s, 1H); ESIMS found C28H20FN7O m/z 490.2 (M+H).
    Figure imgb1200
    Figure imgb1201
     1-Cyclopentyl-N-((5-(3-(4-(4-fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methyl)methanamine 586.
  • Tan solid (13.8 mg, 0.027 mmol, 15.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.11-1.23 (m, 2H), 1.40-1.58 (m, 4H), 1.65-1.74 (m, 2H), 2.04 (quin, J=7.5Hz, 1H), 2.58 (d, J=6.5Hz, 2H), 3.94 (s, 2H), 7.36 (t, J=8.5Hz, 2H), 7.50 (d, J=7Hz, 1H), 7.54 (d, J=7.5Hz, 1H), 8.24 (s, 1H), 8.34-8.42 (m, 3H), 8.65 (s, 1H), 8.97 (d, J=1.5Hz, 1H), 9.13 (d, J=2Hz, 1H), 9.14 (d, J=2Hz, 1H), 13.38 (brs, 1H), 14.36 (brs, 1H); ESIMS found C31H28FN7 m/z 518.0 (M+H).
    Figure imgb1202
     N-(5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide 594.
  • Tan solid (54.7 mg, 0.108 mmol, 61.2% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.32 (s, 9H), 7.32-7.40 (m, 3H), 7.51 (d, J=7.5Hz, 1H), 7.54 (d, J=8Hz, 1H), 8.41 (dd, 6Hz, J=9Hz, 2H), 8.67 (t, J=2Hz, 1H), 8.74 (d, J=2Hz, 1H), 8.92 (d, J=2Hz, 1H), 9.02 (d, J=2.5Hz, 1H), 9.05 (d, J=2Hz, 1H), 9.66 (s, 1H), 13.38 (s, 1H), 14.41 (s, 1H); ESIMS found C29H24FN7O m/z 506.0 (M+H).
    Figure imgb1203
     N-(5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)-2-phenylacetamide 595.
  • Beige solid (15.5 mg, 0.029 mmol, 15.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.78 (s, 2H), 7.23-7.29 (m, 4H), 7.29-7.42 (m, 6H), 7.52-7.61 (m, 1H), 8.00-8.07 (m, 1H), 8.51 (t, J=2Hz, 1H), 8.66 (d, J=2Hz, 1H), 8.77 (d, J=2.5Hz, 1H), ABq, J=2Hz, J=11Hz, 2H), 10.61 (s, 1H), 13.34 (s, 1H), 14.36 (s, 1H); ESIMS found C32H22FN7O m/z 540.3 (M+H).
    Figure imgb1204
     3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 599.
  • Beige solid (6.2 mg, 0.013 mmol, 7.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.73 (brs, 4H), 2.54 (brs, 4H), 3.75 (s, 2H), 7.30-7.41 (m, 4H), 7.43-7.52 (m, 1H), 7.60 (dd, J=2.5Hz, J=7Hz, 1H), 8.05 (s, 1H), 8.08 (t, J=7.5Hz, 1H), 8.58 (s, 1H), 8.89 (d, J=1.5Hz, 1H), 9.00 (d, J=2Hz, 1H), 9.03 (d, J=2Hz, 1H), 13.35 (s, 1H), 14.59 (brs, 1H); ESIMS found C29H24FN7 m/z 490.0 (M+H).
    Figure imgb1205
     N-(5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)butyramide 602.
  • Tan solid (31.9 mg, 0.065 mmol, 35.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.98 (t, J=7Hz, 3H), 1.69 (sex, J=7Hz, 2H), 2.42 (t, J=7.5Hz, 2H), 7.30-7.46 (m, 5H), 7.59 (d, J=7Hz, 1H), 8.09 (t, J=7Hz, 1H), 8.43 (s, 1H), 8.64 (s, 1H), 8.76 (s, 1H), 8.95 (s, 2H), 10.30 (s, 1H), 13.35 (s, 1H), 14.37 (s, 1H); ESIMS found C28H22FN7O m/z 492.1 (M+H).
    Figure imgb1206
     N-(5-(3-(4-(2-Fluorophenyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)cyclobutanecarboxamide 605.
  • Beige solid (60.3 mg, 0.12 mmol, 35.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.81-1.91 (m, 1H), 1.93-2.07 (m, 1H), 2.13-2.25 (m, 2H), 2.25-2.37 (m, 2H), 7.31-7.45 (m, 5H), 7.59 (dd, J=1.5Hz, J=7Hz, 1H), 8.10 (dt, J=2Hz, J=7.5Hz, 1H), 8.53 (t, J=2Hz, 1H), 8.64 (d, J=2Hz, 1H), 8.76 (d, J=2Hz, 1H), 8.92-8.97 (m, 2H), 10.16 (s, 1H), 13.35 (s, 1H), 14.37 (s, 1H); ESIMS found C29H22FN7O m/z 504.2 (M+H).
    Figure imgb1207
     N,N-Dimethyl-5-(3-(4-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-amine 616.
  • Tan solid (11.4 mg, 0.026 mmol, 13.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.09 (s, 6H), 7.59 (d, J=4.58Hz, 2H), 7.72 (dd, J=3Hz, J=5Hz, 2H), 8.03 (brs, 2H), 8.32 (s, 2H), 8.48 (s, 2H), 8.81 (brs, 2H), 13.79 (brs, 1H), 14.56 (brs, 1H); ESIMS found C25H20N8 m/z 433.0 (M+H).
    Figure imgb1208
     N,N-Dimethyl-1-(5-(3-(4-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 621.
  • Dark brown solid (19.6 mg, 0.044 mmol, 23.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.24 (s, 6H), 3.57 (s, 2H), 7.36 (t, J=8Hz, 1H), 7.41 (t, J=7.5Hz, 1H), 7.51 (d, J=7Hz, 1H), 7.55 (t, J=7.5Hz, 2H), 8.11 (d, J=2Hz, 1H), 8.32 (d, J=7.5Hz, 2H), 8.58 (d, 1.5Hz, 1H), 8.98 (d, J=2.5Hz, 1H), 9.07 (d, J=2.5Hz, 1H), 9.14 (d, J=2Hz, 1H), 13.36 (brs, 1H), 14.33 (brs, 1H); ESIMS found C26H22N8 m/z 447.2 (M+H).
    Figure imgb1209
     5-(3-(4-(Pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b] pyridin-5-yl)pyridin-3-amine 635.
  • Brown solid (3.3 mg, 0.008 mmol, 4.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 5.65 (brs, 2H), 7.38 (s, 1H), 7.42 (t, J=7.5Hz, 1H), 7.66 (d, J=8Hz, 1H), 7.71 (d, J=7.5Hz, 1H), 8.05 (s, 1H), 8.22 (s, 1H), 8.41 (d, J=5.5Hz, 2H), 8.73 (d, J=5Hz, 2H), 8.93 (d, J=1.5Hz, 1H), 9.07 (s, 1H), 13.51 (s, 1H), 14.39 (s, 1H); ESIMS found C23H16N8 m/z 405.1 (M+H).
    Figure imgb1210
     5-(4-Methylpyridin-3-yl)-3-(4-(pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine 637.
  • Tan solid (6.8 mg, 0.017 mmol, 18.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.43 (s, 3H), 7.42 (t, J=4.5Hz, 1H), 7.49 (d, J=5Hz, 1H), 7.65 (t, J=7.5Hz, 3H), 8.30 (d, J=6Hz, 2H), 8.55 (d, J=4.5Hz, 1H), 8.62 (d, J=6.5Hz, 2H), 8.76 (d, J=2Hz, 1H), 8.89 (d, J=2Hz, 1H), 13.49 (s, 1H), 14.42 (s, 1H); ESIMS found C24H17N7 m/z 404.2 (M+H).
    Figure imgb1211
     N-Isopropyl-5-(3-(4-(pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-amine 643.
  • Brown solid (2.9 mg, 0.06 mmol, 3.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.20 (d, J=6Hz, 6H), 3.74 (sep, J=6.5Hz, 1H), 5.93 (d, J=8Hz, 1H), 7.26 (s, 1H), 7.41 (t, J=8Hz, 1H), 7.63.74 (sep, J=6.5Hz, 1H), 5.93 (d, J=8Hz, 1H), 7.26 (s, 1H), 7.41 (t, J=8Hz, 1H), 7.6 (dd, J=15Hz, J=7.5Hz, 2H), 8.05 (d, J=2Hz, 1H), 8.17 (d, J=1.5Hz, 1H), 8.36 (d, J=6Hz, 2H), 8.68 (d, J=6Hz, 2H), 8.97 (d, J=2.5Hz, 1H), 9.06 (d, J=2Hz, 1H), 13.49 (s, 1H), 14.38 (s, 1H); ESIMS found C26H22N8 m/z 447.0 (M+H).
    Figure imgb1212
     3,3-Dimethyl-N-(5-(3-(4-(pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)butanamide 647.
  • Beige solid (1.2 mg, 0.002 mmol, 1.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.08 (s, 9H), 2.32 (s, 2H), 7.42 (t, J=8.5Hz, 1H), 7.66 (d, J=8Hz, 1H), 7.71 (d, J=7.5Hz, 1H), 8.40 (d, J=5.5Hz, 2H), 8.62 (s, 1H), 8.72 (d, J=6Hz, 2H), 8.74 (d, J=2Hz, 1H), 8.77 (d, J=2.5Hz, 1H), 9.00 (d, J=2.5Hz, 1H), 9.09 (d, J=2Hz, 1H), 10.28 (s, 1H), 13.52 (s, 1H), 14.45 (s, 1H); ESIMS found C29H26N8O m/z 503.3 (M+H).
    Figure imgb1213
     N-Benzyl-1-(5-(3-(4-(pyridin-4-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 654.
  • Beige solid (26.1 mg, 0.051 mmol, 51.3% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.77 (s, 2H), 3.85 (s, 2H), 7.23 (t, J=7Hz, 1H), 7.32 (t, J=8Hz, 2H), 7.37-7.46 (m, 3H), 7.65 (d, J=8Hz, 1H), 7.69 (d, J=7.5Hz, 1H), 8.28 (s, 1H), 8.39 (dd, J=1.5Hz, J=4.5Hz, 2H), 8.64 (s, 1H), 8.73 (dd, J=1.5Hz, J=4.5Hz, 2H), 8.99 (s, 1H), 9.08 (d, J=2Hz, 1H), 9.18 (d, J=2Hz, 1H), 13.51 (s, 1H), 14.42 (brs, 1H); ESIMS found C31H24N8 m/z 509.6 (M+H).
    Figure imgb1214
     5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine 680.
  • Beige solid (26.4 mg, 0.052 mmol, 30.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.30 (quin, J=7Hz, J=8Hz, 2H), 2.84 (brs, 2H), 3.03 (brs, 2H), 3.87 (s, 2H), 7.35 (s, 1H), 7.41 (t, J=7.5Hz, 2H), 7.72 (brs, 1H), 7.97 (t, J=7.5Hz, 1H), 8.13 (d, J=6Hz, 1H), 8.22 (s, 1H), 8.63 (s, 1H), 8.79 (brs, 1H), 9.01 (s, 1H), 9.06 (d, J=2Hz, 1H), 9.14 (brs, 1H), 14.47 (s, 1H); ESIMS found C28H22F2N8 m/z 509.4 (M+H).
    Figure imgb1215
     N-(5-(3-(4-(Piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)benzamide 691.
  • Brown solid (14.8 mg, 0.029 mmol, 16.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.74 (brs, 6H), 3.56 (brs, 4H), 6.53 (brd, J=7Hz, 1H), 7.02 (brd, J=8Hz, 1H), 7.09 (t, J=8Hz, 1H), 7.59 (t, J=7.5Hz, 2H), 7.66 (t, J=7.5Hz, 1H), 8.05 (d, J=8Hz, 2H), 8.72 (s, 1H), 8.81 (d, J=2Hz, 1H), 8.98 (s, 1H), 9.06 (d, J=2Hz, 1H), 9.14 (s, 1H), 10.64 (s, 1H), 13.06 (s, 1H), 14.26 (s, 1H); ESIMS found C30H26N8O m/z 515.2 (M+H).
    Figure imgb1216
     N-(5-(3-(4-(Piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)pentanamide 698.
  • Brown solid (47.0 mg, 0.095 mmol, 53.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.93 (t, J=7.5Hz, 3H), 1.36 (sex, J=7.5Hz, 2H), 1.55-167 (m, 4H), 1.68-1.81 (m, 4H), 2.40 (t, J=7.5Hz, 2H), 3.59 (brs, 4H), 6.56 (brs, 1H), 7.04 (brs, 1H), 7.10 (t, J=7.5Hz, 1H), 8.59 (s, 1H), 8.70 (d, J=2Hz, 1H), 8.72 (s, 1H), 8.99 (d, J=2Hz, 1H), 9.06 (s, 1H), 10.29 (s, 1H), 13.06 (brs, 1H), 14.27 (s, 1H); ESIMS found C28H30N8O m/z 495.4 (M+H).
    Figure imgb1217
     N-(5-(3-(4-(Piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopentanecarboxamide 701.
  • Brown solid (3.9 mg, 0.008 mmol, 4.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.54-1.63 (m, 4H), 1.63-1.73 (m, 2H), 1.72-1.83 (m, 6H), 1.85-1.95 (m, 2H), 2.87 (quin, J=6.5Hz, 1H), 3.58 (t, J=5Hz, 4H), 6.53 (d, J=8Hz, 1H), 7.01 (d, J=8Hz, 1H), 7.09 (t, J=8Hz, 1H), 8.64 (t, J=2Hz, 1H), 8.71 (dd, J=3.5Hz, J=2Hz, 2H), 9.00 (d, J=2.5Hz, 1H), 9.06 (d, J=2Hz, 1H), 10.28 (s, 1H), 13.03 (s, 1H), 14.25 (s, 1H); ESIMS found C29H30N8O m/z 507.1 (M+H).
    Figure imgb1218
     1-Cyclopentyl-N-((5-(3-(4-(piperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methyl)methanamine 704.
  • Brown solid (10.1 mg, 0.02 mmol, 11.5% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.15-1.25 (m, 2H), 1.43-1.83 (m, 12H), 2.04 (quin, J=7.5Hz, 1H), 2.63 (d, J=6Hz, 2H), 3.55-3.62 (m, 4H), 3.97 (brs, 2H), 6.54 (d, J=8Hz, 1H), 7.02 (d, J=8Hz, 1H), 7.09 (t, J=8Hz, 1H), 8.24 (brs, 1H), 8.65 (s, 1H), 8.96 (s, 1H), 9.05 (d, J=2Hz, 1H), 9.13 (d, J=2Hz, 1H), 13.05 (s, 1H), 14.27 (brs, 1H); ESIMS found C30H34N8 m/z 507.0 (M+H).
    Figure imgb1219
     N,N-Dimethyl-1-(5-(3-(4-(4-methyl-1H-imidazol-1-yl)-1H-benzo[d] imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 719.
  • Light brown solid (12.3 mg, 0.027 mmol, 14.3% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.24 (s, 6H), 2.25 (s, 3H), 3.58 (s, 2H), 7.35 (t, J=8Hz, 1H), 7.48 (t, J=8.5Hz, 2H), 7.96 (s, 1H), 8.13 (s, 1H), 8.59 (d, J=1.5Hz, 1H), 8.74 (s, 1H), 8.96 (d, J=2Hz, 1H), 9.04 (d, J=2Hz, 1H), 9.07 (d, J=2.5Hz, 1H), 13.58 (brs, 1H), 14.44 (brs, 1H); ESIMS found C25H23N9 m/z 450.2 (M+H).
    Figure imgb1220
     N-(5-(3-(4-(4-Methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclohexanecarboxamide 728.
  • Brown solid (30.7 mg, 0.06 mmol, 35.1% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.15-1.36 (m, 3H), 1.45 (dq, J=2.5Hz, J=12Hz, 2H), 1.67 (d, J=12.5Hz, 1H), 1.78 (d, J=12.5Hz, 2H), 1.88 (d, J=11.5Hz, 2H), 2.22 (s, 3H), 2.41 (tt, J=3Hz, J=11.5Hz, 1H), 7.35 (t, J=7.5Hz, 1H), 7.48 (d, J=2Hz, 1H), 7.49 (d, J=2.5Hz, 1H), 8.01 (s, 1H), 8.47 (t, J=2Hz, 1H), 8.70 (d, J=1.5Hz, 2H), 8.87 (d, J=2.5Hz, 1H), 8.96 (d, J=2.5Hz, 1H), 9.02 (d, J=2.5Hz, 1H), 10.23 (s, 1H), 13.59 (s, 1H), 14.46 (s, 1H); ESIMS found C29H27N9O m/z 518.4 (M+H).
    Figure imgb1221
     N-((5-(3-(4-(4-Methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methyl)ethanamine 738.
  • Brown solid (15.2 mg, 0.033 mmol, 17.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.07 (t, J=7.5Hz, 3H), 2.28 (s, 3H), 2.54-2.66 (m, 6H), 3.63 (brs, 4H), 3.86 (s, 2H), 6.54 (d, J=8Hz, 1H), 7.05 (d, J=8Hz, 1H), 7.10 (t, J=8Hz, 1H), 8.16 (s, 1H), 8.62 (d, J=1.5Hz, 1H), 8.92 (d, J=2.5Hz, 1H), 9.05 (d, J=2.5Hz, 1H), 9.06 (d, J=2Hz, 1H), 13.08 (brs, 1H); ESIMS found C26H29N9 m/z 468.2 (M+H).
    Figure imgb1222
     N-(5-(3-(4-(4-Methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclobutanecarboxamide 752.
  • Dark yellow solid (4.1 mg, 0.008 mmol, 2.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.78-1.89 (m, 1H), 1.92-2.05 (m, 1H), 2.11-2.21 (m, 2H), 2.23 (s, 3H), 2.23-2.34 (m, 2H), 2.58 (brs, 4H), 3.63 (brs, 4H), 6.54 (d, J=8Hz, 1H), 7.04 (d, J=8Hz, 1H), 7.10 (t, J=8Hz, 1H), 8.58 (s, 1H), 8.69 (d, J=2Hz, 1H), 8.76 (d, J=2.5Hz, 1H), 8.98 (d, J=2Hz, 1H), 9.01 (d, J=2Hz, 1H), 10.15 (s, 1H), 13.08 (s, 1H), 14.27 (s, 1H); ESIMS found C28H29N9O m/z 507.9 (M+H).
    Figure imgb1223
     5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)-1H-benzo [d] imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine 758.
  • Beige solid (39.6 mg, 0.075 mmol, 43.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.27 (quin, J=8.5Hz, 2H), 2.28 (s, 3H), 2.61 (brs, 4H), 2.78 (t, J=7Hz, 2H), 2.96 (t, J=13Hz, 2H), 3.63 (brs, 4H), 3.81 (s, 2H), 6.54 (d, J=8Hz, 1H), 7.05 (d, J=8Hz, 1H), 7.11 (t, J=8Hz, 1H), 8.11 (s, 1H), 8.61 (d, J=1.5Hz, 1H), 8.95 (d, J=2Hz, 1H), 9.05 (s, 2H), 13.08 (s, 1H), 14.27 (brs, 1H); ESIMS found C28H29F2N9 m/z 530.4 (M+H).
    Figure imgb1224
     5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl) pyridin-3-amine 761.
  • Brown solid (7.9 mg, 0.024 mmol, 11.8% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 6.01 (brs, 1H), 7.20-7.31 (m, 2H), 7.56 (s, 1H), 7.66 (brs, 2H), 8.05 (d, J=1.5Hz, 1H), 8.30 (s, 1H), 8.94 (d, J=1.5Hz, 1H), 8.98 (s, 1H), 13.24 (brs, 1H), 14.41 (s, 1H); ESIMS found C18H13N7 m/z 327.6 (M+H).
    Figure imgb1225
     J=3.5Hz, 2H), 8.22 (d, J=3Hz, 1H), 8.38 (d, J=1.5Hz, 1H), 9.01 (d, J=2Hz, 1H), 9.03 (d, J=2Hz, 1H), 14.40 (s, 1H); ESIMS found C20H17N7 mlz 356.0 (M+H).
    Figure imgb1226
     N-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl) pyridin-3-yl)-3,3-dimethylbutanamide 774.
  • Brown solid (22.3 mg, 0.05 mmol, 30.3% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.07 (s, 9H), 2.29 (s, 2H), 7.24-7.31 (m, 2H), 7.68 (brs, 2H), 8.46 (t, J=2Hz, 1H), 8.75 (d, J=2Hz, 1H), 8.91 (d, J=2.5Hz, 1H), 8.99 (d, J=2Hz, 1H), 9.01 (d, J=2.5Hz, 1H), 10.29 (s, 1H), 14.47 (s, 1H); ESIMS found C24H23N7O mlz 426.2 (M+H).
    Figure imgb1227
     1-(5-(3-(1H-Benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl) pyridin-3-yl)-N-benzylmethanamine 781.
  • Beige solid (21.0 mg, 0.049 mmol, 48.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.77 (s, 2H), 3.85 (s, 2H), 7.18-7.29 (m, 3H), 7.33 (t, J=8Hz, 2H), 7.39 (d, J=7.5Hz, 2H), 7.55 (d, J=8Hz, 1H), 7.77 (d, J=7.5Hz, 1H), 8.20 (s, 1H), 8.60 (d, J=1.5Hz, 1H), 8.89 (d, J=2Hz, 1H), 9.00 (d, J=2Hz, 1H), 9.03 (d, J=2Hz, 1H), 13.17 (s, 1H), 14.27 (brs, 1H); ESIMS found C26H21N7 m/z 432.1 (M+H).
    Figure imgb1228
     N-(5-(3-(4-(Thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo [3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide 785.
  • Brown solid (33.5 mg, 0.072 mmol, 38.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.17 (t, J=7.5Hz, 3H), 2.46 (q, J=7.5Hz, 2H), 7.32 (t, J=7.5Hz, 1H), 7.48 (d, J=8Hz, 1H), 7.64 (d, J=7.5Hz, 1H), 7.68 (dd, J=3.5Hz, J=5Hz, 1H), 8.12 (dd, J=1Hz, J=5Hz, 1H), 8.65 (t, J=2Hz, 1H), 8.68 (dd, J=1Hz, J=3Hz, 1H), 8.75 (d, J=2Hz, 2H), 9.02 (d, J=2Hz, 1H), 9.12 (d, J=2.5Hz, 1H), 10.32 (s, 1H), 13.35 (s, 1H), 14.40 (s, 1H); ESIMS found C25H19N7OS m/z 466.1 (M+H).
    Figure imgb1229
     N-(5-(3-(4-(Thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)isobutyramide 793.
  • Tan solid (17.0 mg, 0.035 mmol, 19.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.20 (d, J=6.5Hz, 6H), 2.71 (sep, J=6.5Hz, 1H), 7.32 (t, J=8Hz, 1H), 7.49 (d, J=8Hz, 1H), 7.64 (d, J=7.5Hz, 1H), 7.68 (dd, J=3.5Hz, J=5Hz, 1H), 8.14 (d, J=4.5Hz, 1H), 8.66 (d, J=2Hz, 1H), 8.68 (d, J=2Hz, 1H), 8.75 (d, J=2Hz, 1H), 8.79 (d, J=2Hz, 1H), 9.02 (d, J=2.5Hz, 1H), 9.12 (d, J=2Hz, 1H), 10.28 (s, 1H), 13.35 (s, 1H), 14.40 (s, 1H); ESIMS found C26H21N7OS m/z 479.8 (M+H).
    Figure imgb1230
     N,N-Dimethyl-1-(5-(3-(4-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)methanamine 797.
  • Brown solid (26.7 mg, 0.059 mmol, 31.0% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.25 (s, 6H), 3.59 (s, 2H), 7.32 (t, J=8Hz, 1H), 7.49 (d, J=8Hz, 1H), 7.63 (d, J=7.5Hz, 1H), 7.68 (dd, J=3Hz, J=5Hz, 1H), 8.11 (dd, J=1Hz, J=5Hz, 1H), 8.15 (s, 1H), 8.59 (d, J=1.5Hz, 1H), 8.74 (dd, J=1.5Hz, J=3Hz, 1H), 9.00 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 9.16 (d, J=2.5Hz, 1H), 13.35 (brs, 1H), 14.38 (brs, 1H); ESIMS found C25H21N7S m/z 452.1 (M+H).
    Figure imgb1231
     5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-3-(4-(thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine 799.
  • Beige solid (55.8 mg, 0.11 mmol, 43.5% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.40 (brs, 2H), 1.47-1.56 (m, 4H), 2.42 (brs, 1H), 3.63 (s, 2H), 7.32 (t, J=7.5Hz, 1H), 7.49 (d; J=8Hz, 1H), 7.63 (d, J=7Hz, 1H), 7.68 (dd, J=5Hz, J=3Hz, 1H), 8.11 (dd, J=1Hz, J=5,5Hz, 1H), 8.13 (s, 1H), 8.59 (d, J=1Hz, 1H), 8.74 (dd, J=1Hz, J=3Hz, 1H), 8.98 (d, J=2Hz, 1H), 9.07 (d, J=2Hz, 1H), 9.16 (d, J=2Hz, 1H), 13.35 (s, 1H), 14.38 (s, 1H) ESIMS found C28H25N7S m/z 492.2 (M+H).
    Figure imgb1232
    Figure imgb1233
     N-(5-(3-(4-(Thiophen-3 -yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)cyclopropanecarboxamide 803.
  • Yellow-white solid (20.2 mg, 0.04 mmol, 56.4% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.85-0.95 (m, 4H), 1.85-1.92 (m, 1H), 7.32 (t, J=8Hz, 1H), 7.49 (d, J=8Hz, 1H), 7.60-7.69 (m, 2H), 8.11 (brs, 1H), 8.64 (s, 1H), 8.67 (s, 1H), 8.75 (s, 1H), 9.01 (d, J=2Hz, 1H), 9.11 (s, 1H), 10.65 (s, 1H), 13.35 (brs, 1H), 14.40 (s, 1H); ESIMS found C26H19N7OS m/z 478.1 (M+H).
    Figure imgb1234
     N-(5-(3-(4-(Furan-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide 818.
  • Brown solid (36.0 mg, 0.075 mmol, 42.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.30 (s, 9H), 7.30 (t, J=7.5Hz, 1H), 7.35 (d, J=1Hz, 1H), 7.45 (d, J=7.5Hz, 1H), 7.53 (d, J=7.5Hz, 1H), 7.78 (t, J=1.5Hz, 1H), 8.59 (t, J=2Hz, 1H), 8.78 (d, J=2Hz, 1H), 8.83 (s, 1H), 8.96 (d, J=2Hz, 1H), 9.02 (d, J=2.5Hz, 1H),9.11 (d, J=2Hz, 1H), 9.62 (s, 1H), 13.32 (s, 1H), 14.40 (s, 1H); ESIMS found C27H23N7O2 m/z 478.1 (M+H).
    Figure imgb1235
     N-(5-(3-(4-(Furan-3-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)butyramide 827.
  • Brown solid (29.6 mg, 0.064 mmol, 36.9% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.96 (t, J=7.5Hz, 3H), 1.68 (sex, J=7.5Hz, 2H), 2.39 (t, J=7Hz, 1H), 7.29 (t, J=8Hz, 1H), 7.36 (d, J=1.5Hz, 1H), 7.45 (d, J=7.5Hz, 1H), 7.53 (d, J=7.5Hz, 1H), 7.79 (t, J=1.5Hz, 1H), 8.57 (d, J=2Hz, 1H), 8.75 (d, J=1.5Hz, 1H), 8.80 (d, J=2Hz, 1H), 8.81 (s, 1H), 8.98 (d, J=2.5Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.31 (s, 1H), 13.32 (s, 1H), 14.40 (s, 1H), ; ESIMS found C26H21N7O2 m/z 464.2 (M+H).
    Figure imgb1236
     5 -(5 -(Pyrrolidin-1-ylmethyl)pyridin-3 -yl)-3 -(4-(thiophen-2-yl)- 1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine 898.
  • Beige solid (15.4 mg, 0.032 mmol, 17.7% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.74 (brs, 4H), 2.52 (brs, 4H), 3.80 (brs, 2H), 7.23 (dd, J=3.5Hz, J=5Hz, 1H), 7.31 (t, J=8Hz, 1H), 7.48 (d, J=7.5Hz, 1H), 7.61 (dd, J=1Hz, J=5Hz, 1H), 7.66 (d, J=7.5Hz, 1H), 8.18 (dd, J=1Hz, J=3.5Hz, 1H), 8.19 (brs, 1H), 8.63 (brs, 1H), 9.01 (brs, 1H), 9.09 (d, J=2Hz, 1H), 9.32 (d, J=2Hz, 1H), 13.42 (s, 1H), 14.40 (s, 1H); ESIMS found C27H23N7S m/z 478.0 (M+H).
    • Example 3.
  • The above synthesized compounds were screened using the assay procedure for Wnt activity described below.
  • Reporter cell lines can be generated by stably transducing cells of cancer cell lines (e.g., colon cancer) with a lentiviral construct that include a wnt-responsive promoter driving expression of the firefly luciferase gene.
  • Lentiviral constructs can be made in which the SP5 promoter, a promoter having eight TCF/LEF binding sites derived from the SP5 promoter, is linked upstream of the firefly luciferase gene. The lentiviral constructs can also include a hygromycin resistance gene as a selectable marker. The SP5 promoter construct can be used to transduce SW480 cells, a colon cancer cell line having a mutated APC gene that generates a truncated APC protein, leading to de-regulated accumulation of β-catenin. A control cell line can be generated using another lentiviral construct containing the luciferase gene under the control of the SV40 promoter which does not require β-catenin for activation.
  • Cultured SW480 cells bearing a reporter construct can be distributed at approximately 10,000 cells per well into 96 well or 384 well plates. Compounds from a small molecule compound library can then be added to the wells in half-log dilutions using a ten micromolar top concentration. A series of control wells for each cell type receive only buffer and compound solvent. Twenty-four to forty hours after the addition of compound, reporter activity for luciferase can be assayed, for example, by addition of the BrightGlo luminescence reagent (Promega) and the Victor3 plate reader (Perkin Elmer). Readings can be normalized to DMSO only treated cells, and normalized activities can then be used in the IC50 calculations. Table 2 shows the activity of selected compounds of the invention. Table 2.
    Compound Wnt inhibition (µM) Compound Wnt inhibition (µM) Compound Wnt inhibition (µM)
    1 0.006 192 1.05 594 0.12
    2 0.038 198 1.13 595 0.354
    2 0.006 209 9.8 599 0.22
    4 0.333 229 0.012 602 0.018
    5 0.0039 238 0.35 605 0.018
    6 0.55 241 0.19 616 1.41
    7 0.006 246 1.27 621 0.036
    8 8.25 249 10 635 0.034
    9 0.0012 254 0.235 637 0.11
    10 0.263 305 7.35 643 0.03
    11 0.099 309 1.02 647 1.52
    12 0.021 325 0.058 654 1.5
    13 0.172 336 0.79 680 0.17
    14 0.138 346 0.056 691 0.187
    15 0.326 352 0.057 698 0.3
    16 0.384 354 0.293 701 0.625
    17 0.55 373 0.07 704 0.81
    18 0.013 376 0.051 719 0.2
    19 0.499 382 0.003 728 0.039
    20 10 440 0.004 738 0.55
    21 0.167 443 0.001 752 0.226
    22 0.032 452 0.048 758 0.048
    23 10 458 0.022 761 0.32
    24 0.021 463 0.098 765 0.027
    25 10 547 0.097 774 0.2
    27 1.78 551 0.033 781 1.44
    28 0.72 552 0.022 785 0.01
    114 0.011 554 0.2 793 0.016
    128 0.09 557 0.053 797 0.032
    142 0.645 560 0.09 799 0.082
    158 0.008 561 0.143 803 0.017
    176 1.55 573 0.082 818 0.05
    178 0.392 581 0.048 827 0.063
    179 1.45 586 0.42 888 0.012
    185 1.32 590 0.02 898 0.12
    • Example 3.
  • Preparation of a parenteral suspension with a compound of Formulas (I) or (II) for the treatment of bone/cartilage diseases. Table 3. Approximate solubility of a compound of Formulas (I) or (II)
    Sample mg/mL pH
    water 0.12
    1 mM HCl 0.72 5.8
    2 mM HCl 1.38 5.5
    3 mM HCl 1.84 5.4
    EtOH 0.56
    Propylene Glycol 2.17
  • Preparation of a 220 µg/mL suspension in 0.5% CMC/0.05% tween 80 begins by dispensing 597 g ± 1 g of Gibco 1X PBS into the 1 L glass bottle. Using a 1 mL sterile syringe, measure 0.3 mL of Tween 80. In a weigh boat, weigh out 3 g ± 0.1 g of Carboxymethyl Cellulose 7LXF PH (CMC). Mix with the Tween80/PBS solution and slowly sprinkle the CMC into the 1 L bottle containing the PBS/Tween mixture (increase mixing speed as necessary). Once visually dispersed and the polymer is hydrated, start heating the container on a heating plate to promote phase inversion (turbidity). Once the solution is cool to the touch, filter NLT 120 mL into the 250 mL glass bottle. Weigh 27 mg of a compound of Formulas (I) or (II) and suspend by mixing with the aid of 120 g of the sterile filtered CMC/tween solution. Fill 2 mL schott glass vials and 13 mm Flurotec coated stoppers (West Pharma) and autoclave the vials at 260°F for NLT 25 minutes.
    • Example 4.
  • Preparation of a parenteral preparation with a compound of Formulas (I) or (II).
  • 10 mg of a compound of Formulas (I) or (II) (or its salt) is dissolved with the aid of 10 mL of propylene glycol (USP grade), using aseptic techniques, sterile filter the solution using a millex GP syringe filter into a sterile glass (type II) container. Before parenteral administration, add 10mL of the above solution in propylene glycol to a vial containing 90 mL of sterile water, mix well.
    • Example 5.
  • Preparation of a suspension for intravitreal injection with a compound of Formulas (I) or (II).
  • Weigh 10 mg of a micronized compound of Formulas (I) or (II) (median particle size of 5 µm) and add slowly while mixing to 100 mL of solution of 0.5% carboxymethyl cellulose (Aqualon 7LXF) and 0.05% tween 80 HP-LQ-MH (Croda) dissolved in PBS (Gibco, pH 7.4). The final suspension is loaded into 2 mL glass vials and terminally sterilized by autoclaving.
  • It is also contemplated to heat sterilize a micronized compound of Formulas (I) or (II) and aseptic mixing with the sterile filtered solution of 0.5% carboxymethyl cellulose (Aqualon 7LXF) and 0.05% tween 80 HP-LQ-MH (Croda) dissolved in PBS (Gibco, pH 7.4).
  • Administration is performed using a 30G needle and a volume of approximately 50 µL for intravitreal injection in rabbits.
    • Example 6.
  • Composition for intratympanic injection with a compound of Formulas (I) or (II).
  • 10 mg of a compound of Formulas (I) or (II) is dissolved with the aid of 100 mL of propylene glycol (USP grade), using aseptic techniques, sterile filter the solution using a millex GP syringe filter into a sterile glass (type II) container. Before parenteral administration, add 10 mL of the above solution in propylene glycol to a vial containing 90 mL of sterile water, mix well.
  • Administration is performed using a 25G needle and a volume of approximately 200 µL for intratympanic injection targeting the round window membrane.
    • Example 7. Primary screening assay for idiopathic pulmonary fibrosis (IPF).
  • Compounds of Formulas (I) or (II) were screened in a β-catenin-based reporter assay in a transformed human bronchial epithelial cell line (NL-20). The results shown in Table 4 demonstrated that compounds of Formulas (I) or (II) are able to inhibit β-catenin activity in these cells, supporting the drug's mechanism of action for the treatment of idiopathic pulmonary fibrosis (IPF). Compounds of Formulas (I) or (II) are significantly more potent than ICG-001, a small molecule β-catenin inhibitor [Proc. Natl. Acad. Sci. U.S.A (2010), 107(32), 14309-14314]. Table 4.
    Compound NL-20 β-catenin reporter assay (IC50, µM) Compound NL-20 β-catenin reporter assay (IC50, µM)
    ICG-001 (β-catenin inhibitor) 7 11 0.21
    5 0.175 12 0.31
    7 1.9 14 2.03
    9 0.067 18 0.44
    10 0.247 452 1.09
    • Example 8.
  • Preparation of a composition for pulmonary delivery with a compound of Formulas (I) or (II) for the treatment of pulmonary fibrosis.
  • Weigh 100 mg of a compound of Formulas (I) or (II) (or its salt) an added slowly while mixing to 100 mL of solution of 1.5% dextrose (or lactose) + 0.05% tyloxapol. The final solution is sterile filter the solution using a millex GP syringe filter.
  • Administration is performed using a jet nebulizer (Pari LC plus) or an aerodose nebulizer.
  • C57B1/6 mice were dosed for 30 minutes via a nose only chamber (CH Technology) at a flow rate of 15 LPM, particle size distribution and dose was measured by a 7 stage impactor (1 LPM) placed in one of the ports. A median aerosol particle size of 1.2 µm with a GSD of 1.8 µm was obtained and a dosing rate of 1.5 µM/min/mouse. Table 5.
    Concentrations of a compound of Formulas (I) or (II) in Mice (C57B1/6)
    Inhalation Conc. (ng/mL)
    Time Point (h) Plasma Lung Ratio
    0.25 21.9 467.2 21.3
    2 0.8 400.1 500.1
    6 8.8 392.5 44.6
    23 0.03 260.7 8690
  • A diluted formulation of 0.5 mg/mL of compound of Formulas (I) or (II) was nebulized for 10 and 30 minutes to bleomycin-induced pulmonary fibrotic C57B1/6 mice. Bleomycin is a chemotherapeutic agent which use has been shown to cause pulmonary fibrosis in humans. As a result, it became widely used as a research tool to induce and study pulmonary fibrosis in animals [Walters, D.M. and Kleeberger, S.R., "Mouse models of bleomycin-induced pulmonary fibrosis" Current Protocols in Pharmacology (2008) Chapter 5: Unit 5.46, 1-17]. Male C57B1/6 mice were anesthetized and 2U/kg Bleomycin (Henry Schien) was orophrayngeally administered. After 7 days, the compound of Formulas (I) or (II) was delivered via a nose only chamber (CH Technology) at a flow rate of 20 LPM daily for 30 minutes for 13 days. After the last dose, 13 days, the animals were sacrificed, and their lungs were perfused and with 10% buffered formalin and processed for tissue histology. The plasma was obtained and published biomarkers of disease, MMP-7, TIMP-1 and TGF-β, 1 were evaluated by ELISA [ British Journal of Pharmacology (2010), 160(7), 1699-1713; American journal of respiratory and critical care medicine (2012), 185(1), 67-76]. H&E sections of the lungs and scored in a blinded fashion according to the Ashcroft system to evaluate pulmonary fibrosis [Biotechniques (2008), 44(4), 507-517]. A reduction in pulmonary fibrosis and plasma biomarkers were demonstrated in Compound-treated animals (Table 6). Table 6.
    Treatment Grade of Fibrosis-Ashcroft Score MMP-7 levels (ng/mL) TIMP-1 levels (ng/mL) TGF-β levels (ng/mL)
    PBS/no dose 0.25 10.0 1203 10.0
    Bleomycin/vehicle 3.04 13.6 2763 14.5
    Bleomycin/ 10 min aerosol of a compound of Formulas (I) or (II) 3.52 10.7 2023 14.2
    Bleomycin/ 30 min aerosol of a compound of Formulas (I) or (II) 2.08* 9.4** 1958 9.7
    *p<0.05 vs Bleo/Vehicle, **p=0.035 vs Bleo/Vehicle
    • Example 9. Preparation of a suspension of drug-eluting material with a compound of Formulas (I) or (II).
    • Solution 1 (PLGA containing active): Weigh 425mg of PLGA 50:50 (PLGA 0.55-0.75, Lactel B6010-2P) + 4.5 mg of a compound of Formulas (I) or (II) + 4mL of dichloromethane, mix well to dissolve.
    • Solution 2 (1% PVA solution): Add 40 mL of DI water, then add 413 mg of polyvinyl alcohol (Sigma 87-89% hydrolyzed, PN 363170-25), mix to dissolve then sterile filter through a 0.22 µ PES syringe filter (Millipore Millex GP).
  • PLGA microparticle formation: Add 20 mL of solution 2 into a clean sterile container, while mixing (high speed mixing) slowly add the entire 4 mL of solution 1 to solution 2.
  • The term "comprising" as used herein is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
  • The present disclosure will now be further defined in the following paragraphs:
    1. 1. A compound or pharmaceutically acceptable salt or prodrug thereof having the structure of Formula I:
      Figure imgb1237
       wherein:
      • R1 and R2 are independently selected from the group consisting of H, lower alkyl, halide, -(C1-9 alkyl)naryl(R6)q, -(C1-9alkyl)nheteroaryl(R7)q, -(C1-9alkyl)nheterocyclyl(R8)q, -(C1-9alkyl)nN(R9)2, -OR10 and -NHC(=O)R11;
      • R3 is selected from the group consisting of H, halide and lower alkyl;
      • with the proviso that at least two of R1, R2 and R3 are H;
      • R4 and R5 are independently selected from the group consisting of H, - C(=O)N(R12)2, -aryl(R13)q, -heterocyclyl(R14)q, and -heteroaryl(R15)q;
      • with the proviso that at least one of R4 and R5 is H;
      • each R6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
      • each R7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
      • each R8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, -(C1-3 alkyl)naryl(R6)q, and -C1-4 alkyl;
      • each R9 is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl and -(C1-9alkyl)N(R16)2;
      • alternatively, two adjacent R9 or two adjacent R12, may be taken together with the atoms to which they are attached to form a heterocyclyl(R17)q;
      • R10 is selected from the group consisting of H, -CF3, -(C1-3 alkyl)naryl(R6)q, and-C1-9 alkyl;
      • R11 is selected from the group consisting of -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl, -C1-9 alkyl and -CF3;
      • each R12 is independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q and -C1-9 alkyl;
      • each R13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, -CF3, CN, -(C1-3 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
      • each R14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3 and CN;
      • each R15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3, CN, -C(=O)(C1-3 alkyl), -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
      • each R16 is independently selected from the group consisting of H and lower alkyl;
      • each R17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q, and -C1-9 alkyl;
      • each R18 is a lower alkyl;
      • A is N or C;
      • with the proviso that if A is N then R2 is nil;
      • each q is an integer of 1 to 5;
      • each n is an integer of 0 or 1; and
      • with the proviso that Formula I is not a structure selected from the group consisting of:
        Figure imgb1238
        Figure imgb1239
        Figure imgb1240
        Figure imgb1241
        Figure imgb1242
        Figure imgb1243
        Figure imgb1244
        Figure imgb1245
        Figure imgb1246
        Figure imgb1247
        Figure imgb1248
        Figure imgb1249
        Figure imgb1250
        Figure imgb1251
    2. 2. The compound of paragraph 1 wherein aryl is phenyl.
    3. 3. The compound of paragraph 1 wherein heteroaryl is pyridinyl.
    4. 4. The compound of paragraph 1 wherein heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
    5. 5. The compound of paragraph 1 wherein R2 is selected from the group consisting of H, -(C1-9 alkyl)nheterocyclyl(R8)q, -NHC(=O)R11 and -(C1-9 alkyl)nN(R9)2 and R1 and R3 are both H.
    6. 6. The compound of paragraph 5 wherein R2 is -CH2N(R9)2 or -N(R9)2.
    7. 7. The compound of paragraph 6 wherein R9 is independently selected from the group consisting of H, Me, Et, -CH2phenyl and -CH2carbocyclyl.
    8. 8. The compound of paragraph 5 wherein R2 is -NHC(=O)R11.
    9. 9. The compound of paragraph 8 wherein R11 is selected from the group consisting of -C1-5 alkyl, carbocyclyl, phenyl(R6)q, and -CH2phenyl(R6)q.
    10. 10. The compound as in any of paragraphs 6-9, in which R4 is phenyl(R13)q.
    11. 11. The compound as in any of paragraphs 6-9, in which R4 is - heterocyclyl(R14)q.
    12. 12. The compound as in any of paragraphs 6-9, in which R4 is -heteroaryl(R15)q.
    13. 13. The compound of paragraph 10 wherein R13 is one substituent attached to the phenyl comprising a fluorine atom.
    14. 14. The compound of paragraph 10 wherein R13 is two substituents each attached to the phenyl comprising a fluorine atom and either a -(CH2)nN(R5)2 or a - (CH2)nNHSO2R18.
    15. 15. The compound of paragraph 11 wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; and the R14 is H or Me.
    16. 16. The compound of paragraph 12 wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; and R15 is lower alkyl or halide.
    17. 17. The compound of paragraph 1 having a structure selected from the group consisting of:
      Figure imgb1252
      Figure imgb1253
      Figure imgb1254
      Figure imgb1255
      Figure imgb1256
      Figure imgb1257
      Figure imgb1258
      Figure imgb1259
      Figure imgb1260
      Figure imgb1261
      Figure imgb1262
      Figure imgb1263
      Figure imgb1264
      Figure imgb1265
      Figure imgb1266
      Figure imgb1267
      Figure imgb1268
      Figure imgb1269
      Figure imgb1270
      Figure imgb1271
      Figure imgb1272
      Figure imgb1273
      Figure imgb1274
      Figure imgb1275
      Figure imgb1276
      Figure imgb1277
      Figure imgb1278
      Figure imgb1279
      Figure imgb1280
      Figure imgb1281
      Figure imgb1282
      Figure imgb1283
      Figure imgb1284
      Figure imgb1285
      Figure imgb1286
      Figure imgb1287
      Figure imgb1288
      Figure imgb1289
      Figure imgb1290
      Figure imgb1291
      Figure imgb1292
      Figure imgb1293
      Figure imgb1294
      Figure imgb1295
      Figure imgb1296
      Figure imgb1297
      Figure imgb1298
      Figure imgb1299
      Figure imgb1300
      Figure imgb1301
      Figure imgb1302
      Figure imgb1303
      Figure imgb1304
      Figure imgb1305
      Figure imgb1306
      Figure imgb1307
      Figure imgb1308
      Figure imgb1309
      Figure imgb1310
      Figure imgb1311
      Figure imgb1312
      Figure imgb1313
      Figure imgb1314
      Figure imgb1315
      Figure imgb1316
      Figure imgb1317
      Figure imgb1318
      Figure imgb1319
      Figure imgb1320
      Figure imgb1321
      Figure imgb1322
      Figure imgb1323
      Figure imgb1324
      Figure imgb1325
      Figure imgb1326
      Figure imgb1327
      Figure imgb1328
      Figure imgb1329
      Figure imgb1330
      Figure imgb1331
      Figure imgb1332
      Figure imgb1333
      Figure imgb1334
      Figure imgb1335
      Figure imgb1336
      Figure imgb1337
      Figure imgb1338
      Figure imgb1339
      Figure imgb1340
      Figure imgb1341
      Figure imgb1342
      Figure imgb1343
      Figure imgb1344
      Figure imgb1345
      Figure imgb1346
      Figure imgb1347
      Figure imgb1348
      Figure imgb1349
      Figure imgb1350
      Figure imgb1351
      Figure imgb1352
      Figure imgb1353
      Figure imgb1354
      Figure imgb1355
      Figure imgb1356
      Figure imgb1357
      Figure imgb1358
      Figure imgb1359
      Figure imgb1360
      Figure imgb1361
      Figure imgb1362
      Figure imgb1363
      Figure imgb1364
      Figure imgb1365
      Figure imgb1366
      Figure imgb1367
      Figure imgb1368
      Figure imgb1369
      Figure imgb1370
      Figure imgb1371
      Figure imgb1372
      Figure imgb1373
      Figure imgb1374
      Figure imgb1375
      Figure imgb1376
       and
      Figure imgb1377
    18. 18. A compound or pharmaceutically acceptable salt or prodrug thereof having the structure of Formula II:
      Figure imgb1378
       wherein:
      • R1 and R2 are independently selected from the group consisting of H, lower alkyl, halide, -(C1-9 alkyl)naryl(R6)q, -(C1-9 alkyl)nheteroaryl(R7)q, -(C1-9 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2, -OR10 and -NHC(=O)R11;
      • R3 is selected from the group consisting of H, halide and lower alkyl;
      • with the proviso that at least two of R1, R2 and R3 are H;
      • R4 and R5 are independently selected from the group consisting of H, - C(=O)N(R12)2, -aryl(R13)q, -heterocyclyl(R14)q, and -heteroaryl(R15)q;
      • with the proviso that at least one of R4 and R5 is H;
      • each R6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
      • each R7 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
      • each R8 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, -(C1-3 alkyl)naryl(R6)q, and -C1-4 alkyl;
      • each R9 is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl and -(C1-9 alkyl)N(R16)2;
      • alternatively, two adjacent R9 or two adjacent R12, may be taken together with the atoms to which they are attached to form a heterocyclyl(R17)q;
      • R10 is selected from the group consisting of H, -CF3, -(C1-3 alkyl)naryl(R6)q, and-C1-9 alkyl;
      • R11 is selected from the group consisting of -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl, -C1-9 alkyl and -CF3;
      • each R12 is independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q and -C1-9 alkyl;
      • each R13 is a substituent attached to the aryl ring and independently selected from the group consisting of H, halide, -CF3, CN, -(C1-3 alkyl)nheterocyclyl(R8)q, -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
      • each R14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3 and CN;
      • each R15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3, CN, -C(=O)(C1-3 alkyl), -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
      • each R16 is independently selected from the group consisting of H and lower alkyl;
      • each R17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q, and -C1-9 alkyl;
      • each R18 is a lower alkyl;
      • A is N or C;
      • with the proviso that if A is N then R2 is nil;
      • each q is an integer of 1 to 5;
      • each n is an integer of 0 or 1; and
      • with the proviso that Formula II is not a structure selected from the group consisting of:
        Figure imgb1379
        Figure imgb1380
        Figure imgb1381
        Figure imgb1382
        Figure imgb1383
        Figure imgb1384
        Figure imgb1385
        Figure imgb1386
        Figure imgb1387
        Figure imgb1388
        Figure imgb1389
        Figure imgb1390
        Figure imgb1391
    19. 19. The compound of paragraph 18 wherein aryl is phenyl.
    20. 20. The compound of paragraph 18 wherein heteroaryl is pyridinyl.
    21. 21. The compound of paragraph 18 wherein heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.
    22. 22. The compound of paragraph 18 wherein R2 is selected from the group consisting of H, -(C1-9 alkyl)nheterocyclyl(R8)q, -NHC(=O)R11 and -(C1-9 alkyl)nN(R9)2 and R1 and R3 are both H.
    23. 23. The compound of paragraph 22 wherein R2 is -CH2N(R9)2 or -N(R9)2.
    24. 24. The compound of paragraph 23 wherein R9 is independently selected from the group consisting of H, Me, Et, -CH2phenyl and -CH2carbocyclyl.
    25. 25. The compound of paragraph 22 wherein R2 is -NHC(=O)R11.
    26. 26. The compound of paragraph 25 wherein R11 is selected from the group consisting of -C1-5 alkyl, carbocyclyl, phenyl(R6)q, and -CH2phenyl(R6)q.
    27. 27. The compound as in any of paragraphs 23-26, in which R4 is phenyl(R13)q.
    28. 28. The compound as in any of paragraphs 23-26, in which R4 is - heterocyclyl(R14)q.
    29. 29. The compound as in any of paragraphs 23-26, in which R4 is - heteroaryl(R15)q.
    30. 30. The compound of paragraph 27 wherein R13 is one substituent attached to the phenyl comprising a fluorine atom.
    31. 31. The compound of paragraph 27 wherein R13 is two substituents each attached to the phenyl comprising a fluorine atom and either a -(CH2)nN(R5)2 or a - (CH2)nNHSO2R18.
    32. 32. The compound of paragraph 28 wherein the heterocyclyl is selected from the group consisting of piperazinyl and piperidinyl; and the R14 is H or Me.
    33. 33. The compound of paragraph 29 wherein the heteroaryl is selected from the group consisting of pyridinyl, furyl, thiophenyl and imidazolyl; and R15 is lower alkyl or halide.
    34. 34. The compound of paragraph 18 having a structure selected from the group consisting of:
      Figure imgb1392
      Figure imgb1393
      Figure imgb1394
      Figure imgb1395
      Figure imgb1396
      Figure imgb1397
      Figure imgb1398
      Figure imgb1399
      Figure imgb1400
      Figure imgb1401
      Figure imgb1402
      Figure imgb1403
      Figure imgb1404
      Figure imgb1405
      Figure imgb1406
      Figure imgb1407
      Figure imgb1408
      Figure imgb1409
      Figure imgb1410
      Figure imgb1411
      Figure imgb1412
      Figure imgb1413
      Figure imgb1414
      Figure imgb1415
      Figure imgb1416
      Figure imgb1417
      Figure imgb1418
      Figure imgb1419
      Figure imgb1420
      Figure imgb1421
      Figure imgb1422
      Figure imgb1423
      Figure imgb1424
      Figure imgb1425
      Figure imgb1426
      Figure imgb1427
      Figure imgb1428
      Figure imgb1429
      Figure imgb1430
      Figure imgb1431
      Figure imgb1432
      Figure imgb1433
      Figure imgb1434
      Figure imgb1435
      Figure imgb1436
      Figure imgb1437
      Figure imgb1438
      Figure imgb1439
      Figure imgb1440
      Figure imgb1441
      Figure imgb1442
      Figure imgb1443
      Figure imgb1444
      Figure imgb1445
      Figure imgb1446
      Figure imgb1447
      Figure imgb1448
      Figure imgb1449
      Figure imgb1450
      Figure imgb1451
      Figure imgb1452
      Figure imgb1453
      Figure imgb1454
      Figure imgb1455
      Figure imgb1456
      Figure imgb1457
      Figure imgb1458
      Figure imgb1459
      Figure imgb1460
      Figure imgb1461
      Figure imgb1462
      Figure imgb1463
      Figure imgb1464
      Figure imgb1465
      Figure imgb1466
      Figure imgb1467
      Figure imgb1468
      Figure imgb1469
      Figure imgb1470
      Figure imgb1471
      Figure imgb1472
      Figure imgb1473
      Figure imgb1474
      Figure imgb1475
      Figure imgb1476
      Figure imgb1477
      Figure imgb1478
      Figure imgb1479
      Figure imgb1480
      Figure imgb1481
      Figure imgb1482
      Figure imgb1483
      Figure imgb1484
      Figure imgb1485
      Figure imgb1486
      Figure imgb1487
      Figure imgb1488
      Figure imgb1489
      Figure imgb1490
      Figure imgb1491
      Figure imgb1492
      Figure imgb1493
      Figure imgb1494
      Figure imgb1495
      Figure imgb1496
      Figure imgb1497
      Figure imgb1498
      Figure imgb1499
      Figure imgb1500
      Figure imgb1501
      Figure imgb1502
      Figure imgb1503
      Figure imgb1504
      Figure imgb1505
      Figure imgb1506
      Figure imgb1507
      Figure imgb1508
      Figure imgb1509
      Figure imgb1510
      Figure imgb1511
       and
      Figure imgb1512
    35. 35. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any of the paragraphs 1 or 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
    36. 36. A method of treating a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one compound according to any of the paragraphs 1 or 18, or a pharmaceutically acceptable salt thereof.
    37. 37. A method of paragraph 36, wherein the disorder or disease is cancer.
    38. 38. A method of paragraph 36, wherein the disorder or disease is diabetic retinopathy.
    39. 39. A method of paragraph 36, wherein the disorder or disease is pulmonary fibrosis.
    40. 40. A method of paragraph 36, wherein the disorder or disease is idiopathic pulmonary fibrosis (IPF).
    41. 41. A method of paragraph 36, wherein the disorder or disease is rheumatoid arthritis.
    42. 42. A method of paragraph 36, wherein the disorder or disease is scleroderma.
    43. 43. A method of paragraph 36, wherein the disorder or disease is a mycotic or viral infection.
    44. 44. A method of paragraph 36, wherein the disorder or disease is a bone or cartilage disease.
    45. 45. A method of paragraph 36, wherein the disorder or disease is Alzheimer's disease.
    46. 46. A method of paragraph 36, wherein the disorder or disease is dementia.
    47. 47. A method of paragraph 36, wherein the disorder or disease is Parkinson's disease.
    48. 48. A method of paragraph 36, wherein the disorder or disease is lung disease.
    49. 49. A method of paragraph 36, wherein the disorder or disease is osteoarthritis.
    50. 50. A method of paragraph 36, wherein the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Mullerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
    51. 51. The method of paragraph 36, wherein the patient is a human.
    52. 52. The method of paragraph 37, wherein the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer leukemia, lymphoma, sarcoma and ovarian cancer.
    53. 53. The method of paragraph 36, wherein the compound inhibits one or more proteins in the Wnt pathway.
    54. 54. The method of paragraph 51, wherein the compound inhibits signaling induced by one or more Wnt proteins.
    55. 55. The method of paragraph 52, wherein the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.
    56. 56. The method of paragraph 36, wherein the compound inhibits a kinase activity.
    57. 57. A method of treating a disease or disorder mediated by the Wnt pathway in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one compound according to any of the paragraphs 1 or 18, or a pharmaceutically acceptable salt thereof.
    58. 58. The method of paragraph 55, wherein the compound inhibits one or more Wnt proteins.
    59. 59. A method of treating a disease or disorder mediated by kinase activity in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one compound according to any of the paragraphs 1 or 18, or a pharmaceutically acceptable salt thereof.
    60. 60. The method of paragraph 57, wherein the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.
    61. 61. A method of inhibiting the activity of a protein kinase receptor, the method comprising contacting the receptor with an effective amount of at least one compound according to any of the paragraphs 1 or 18, or a pharmaceutically acceptable salt thereof.
    62. 62. A method of treating a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one compound according to any of the paragraphs 1 or 18, or a pharmaceutically acceptable salt thereof.
    63. 63. A method of preventing or reducing angiogenesis in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one compound according to any of the paragraphs 1 or 18, or a pharmaceutically acceptable salt thereof.
    64. 64. A method of preventing or reducing abnormal cellular proliferation in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one compound according to any of the paragraphs 1 or 18, or a pharmaceutically acceptable salt thereof.
    65. 65. A method of treating a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprising administering to the patient a pharmaceutical composition comprising one or more of the compounds of either paragraph 1 or 18 in combination with a pharmaceutically acceptable carrier and one or more other agents.

Claims (18)

  1. A compound or pharmaceutically acceptable salt thereof having the structure of Formula I:
    Figure imgb1513
     wherein:
    R2 is -NHC(=O)R11;
    R1 and R3 are H;
    R4 is independently selected from the group consisting of -piperidinyl(R14)q, -furyl(R15)q, -thiophenyl(R15)q, and -imidazolyl(R15)q;
    R5 is H;
    each R6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
    each R9 is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl and -(C1-9 alkyl)N(R16)2;
    alternatively, two adjacent R9, may be taken together with the atoms to which they are attached to form a heterocyclyl(R17)q;
    R11 is selected from the group consisting of -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl, -C1-9 alkyl and -CF3;
    each R14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -C1-3 alkyl, halide, -CF3 and CN;
    each R15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C1-3 alkyl, halide, -CF3, CN, -C(=O)(C1-3 alkyl), -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
    each R16 is independently selected from the group consisting of H and -C1-3 alkyl;
    each R17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q, and -C1-9 alkyl;
    each R18 is -C1-3 alkyl;
    A is N or C;
    with the proviso that if A is N then R2 is nil;
    each q is an integer of 1 to 5; and
    each n is an integer of 0 or 1.
  2. The compound of claim 1, wherein R11 is selected from the group consisting of -C1-5 alkyl, carbocyclyl, phenyl(R6)q, and -CH2phenyl(R6)q.
  3. The compound according to any one of claims 1-2, wherein R4 is -furyl(R15)q.
  4. The compound according to any one of claims 1-2, wherein R4 is -thiophenyl(R15)q.
  5. The compound according to any one of claims 1-2, wherein R4 is -imidazolyl(R15)q.
  6. The compound according to any one of claims 1-5, wherein R15 is -C1-3 alkyl or halide.
  7. The compound of claim 1 having a structure selected from the group consisting of:
    Figure imgb1514
    Figure imgb1515
    Figure imgb1516
    Figure imgb1517
    Figure imgb1518
    Figure imgb1519
    Figure imgb1520
    Figure imgb1521
    Figure imgb1522
    Figure imgb1523
    Figure imgb1524
    Figure imgb1525
    Figure imgb1526
    Figure imgb1527
    Figure imgb1528
    Figure imgb1529
    Figure imgb1530
    Figure imgb1531
    Figure imgb1532
    Figure imgb1533
    Figure imgb1534
    Figure imgb1535
    Figure imgb1536
    Figure imgb1537
    Figure imgb1538
    Figure imgb1539
    Figure imgb1540
    Figure imgb1541
     or a pharmaceutically acceptable salt thereof.
  8. A compound or pharmaceutically acceptable salt thereof having the structure of Formula II:
    Figure imgb1542
     wherein:
    R2 is -NHC(=O)R11;
    R1 and R3 are H;
    R4 is independently selected from the group consisting of -piperidinyl(R14)q, -furyl(R15)q, -thiophenyl(R15)q, and -imidazolyl(R15)q;
    R5 is H;
    each R6 is a substituent attached to the aryl ring and independently selected from the group consisting of H, -C1-9 alkyl, halide, CF3 and CN;
    each R9 is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl and -(C1-9 alkyl)N(R16)2;
    alternatively, two adjacent R9 or two adjacent R12, may be taken together with the atoms to which they are attached to form a heterocyclyl(R17)q;
    R10 is selected from the group consisting of H, -CF3, -(C1-3 alkyl)naryl(R6)q, and -C1-9 alkyl;
    R11 is selected from the group consisting of -(C1-3 alkyl)naryl(R6)q, -(C1-3 alkyl)ncarbocyclyl, -C1-9 alkyl and -CF3;
    each R12 is independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q and -C1-9 alkyl;
    each R14 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -C1-3 alkyl, halide, -CF3 and CN;
    each R15 is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, -C1-3 alkyl, halide, -CF3, CN, -C(=O)(C1-3 alkyl), -(C1-9 alkyl)nN(R9)2 and -(C1-9 alkyl)nNHSO2R18;
    each R16 is independently selected from the group consisting of H and lower alkyl;
    each R17 is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, -(C1-9 alkyl)naryl(R6)q, and -C1-9 alkyl;
    each R18 is -C1-3 alkyl;
    A is N or C;
    with the proviso that if A is N then R2 is nil;
    each q is an integer of 1 to 5; and
    each n is an integer of 0 or 1.
  9. The compound of claim 8, wherein R11 is selected from the group consisting of -C1-5 alkyl, carbocyclyl, phenyl(R6)q, and -CH2phenyl(R6)q.
  10. The compound according to any one of claims 8-9, wherein R4 is -furyl(R15)q.
  11. The compound according to any one of claims 8-9, wherein R4 is -thiophenyl(R15)q.
  12. The compound according to any one of claims 8-9, wherein R4 is -imidazolyl(R15)q.
  13. The compound according to any one of claims 8-12, wherein R15 is -C1-3 alkyl or halide.
  14. The compound of claim 8 having a structure selected from the group consisting of:
    Figure imgb1543
    Figure imgb1544
    Figure imgb1545
    Figure imgb1546
    Figure imgb1547
    Figure imgb1548
    Figure imgb1549
    Figure imgb1550
    Figure imgb1551
    Figure imgb1552
    Figure imgb1553
    Figure imgb1554
    Figure imgb1555
    Figure imgb1556
    Figure imgb1557
    Figure imgb1558
    Figure imgb1559
    Figure imgb1560
    Figure imgb1561
    Figure imgb1562
    Figure imgb1563
    Figure imgb1564
    Figure imgb1565
    Figure imgb1566
    Figure imgb1567
    Figure imgb1568
    Figure imgb1569
    Figure imgb1570
     and
    Figure imgb1571
     or a pharmaceutically acceptable salt thereof.
  15. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of the claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  16. A compound according to any of claims 1-14, or a pharmaceutically acceptable salt thereof, for use in treating a disorder or disease in a patient, wherein the patient is human, and. wherein the disorder or disease is selected from: diabetic retinopathy, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), rheumatoid arthritis, scleroderma, a mycotic or viral infection, a bone or cartilage disease, Alzheimer's disease, dementia, Parkinson's disease, osteoarthritis, lung disease and cancer, wherein the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, sarcoma, and ovarian cancer.
  17. The compound for use of claim 16, wherein the disorder or disease is pulmonary fibrosis.
  18. The compound for use of claim 16, wherein the disorder or disease is idiopathic pulmonary fibrosis (IPF).
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